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Our winners and their projects

This is the search engine for the Rare Diseases Foundation's award winners since 2012.

It is very simple, enter the first letters of a researcher's name or a disease in the search bar on the right. You can also sort the items in the table.

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Budget yearProject ownerCityProject financierDisease group and/or diseaseProject titleProject summaryCall for projects
2012Andreas HARTMANN Paris Foundation For Rare DiseasesTourette syndromeIdentification of variants and genes involved in Gilles de la Tourette syndrome -High throughput sequencing 2012 - 1
2012Cecile JULIERParisFoundation For Rare DiseasesNeonatal diabetes mellitusIdentification of a gene responsible for syndromic neonatal diabetes -High throughput sequencing 2012 - 1
2012Cecile SAINT-MARTINParisFoundation For Rare DiseasesAutosomal dominant hyperinsulinismIdentification of the gene(s) responsible for dominant congenital diazoxide-responsive hyperinsulinism in a large family -High throughput sequencing 2012 - 1
2012Celine BOUCHET-SERAPHIN ParisFoundation For Rare DiseasesCobblestone lissencephalyIdentification of a novel gene responsible for lissencephaly type II in a consanguineous multiplex family -High throughput sequencing 2012 - 1
2012Christel THAUVIN-ROBINET DijonFoundation For Rare DiseasesOrofaciodigital syndromeIdentification in the gene(s) implicated in OFD syndrome with median defects -High throughput sequencing 2012 - 1
2012Cyril GOIZETBordeaux Foundation For Rare DiseasesLipodystrophy and leukodystrophy syndromeIdentification of a gene involved in a new syndrome associating lipodystrophy and leukodystrophy (LLD syndrome) - High throughput sequencing 2012 - 1
2012Jeanne AMIELParisFoundation For Rare DiseasesNeurocristopathyIdentification of the molecular bases of a rare neurocristopathy leading to congenital malformation and tumour predisposition -High throughput sequencing 2012 - 1
2012Jerôme BERTHERATParisFoundation For Rare DiseasesMacronodular adrenal hyperplasiaGenetic of macronodular adrenocortical hyperplasia (GENEHYPER) -High throughput sequencing 2012 - 1
2012Karine POIRIERParisFoundation For Rare DiseasesSubcortical band heterotopiaIdentification of new genes involved in subcortical band heterotopia -High throughput sequencing 2012 - 1
2012Marc BARTOLIMarseilleFoundation For Rare DiseasesInclusion Body Myositis, Paget disease and Fronto-temporal Dementia/Amyotrophic Lateral SclerosisIdentification of a disease-causing gene for IBMPFD / ALS (Inclusion Body Myositis, Paget disease and Fronto-temporal Dementia/Amyotrophic Lateral Sclerosis) -High throughput sequencing 2012 - 1
2012Nicolas CHASSAINGToulouseFoundation For Rare DiseasesAnophthalmia - microphthalmiaIdentification of new anophthalmic/microphthalmic genes by exome sequencing -High throughput sequencing 2012 - 1
2012Pascale GUICHENEY ParisFoundation For Rare DiseasesIdiopathic ventricular fibrillation- Brugada syndromeIdentification of a new gene responsible for idiopathic ventricular fibrillation associated with short-coupled variant of torsade de pointes -High throughput sequencing 2012 - 1
2012Patrice BOUVAGNETLyon Foundation For Rare DiseasesHypoplastic left heart syndromeHypoplastic Left Heart Syndrome (HLHS) -High throughput sequencing 2012 - 1
2012Rima NABBOUTParisFoundation For Rare DiseasesEpilepsy with myoclonic-astatic seizuresExome sequencing to identify genes associated with myoclonic astatic epilepsy -High throughput sequencing 2012 - 1
2012Sandrine VUILAUMIER-BARROT Paris Foundation For Rare DiseasesType I congenital disorder of glycosylationExome sequencing of one CDG Ix patient (congenital disorder of glycosylation type I) in a family with one healthy sibling -High throughput sequencing 2012 - 1
2012Sandrine VUILLAUMIER-BARROTParisFoundation For Rare DiseasesType I congenital disorder of glycosylationExome sequencing of one CDG Ix patient (congenital disorder of glycosylation type I) presenting with a novel biochemical phenotype -High throughput sequencing 2012 - 1
2012Agnes BLOCH-ZUPANIllkirchFoundation For Rare DiseasesEnamel knot and dental cusps anomalyMorphodent: Identification of a gene involved in the enamel knot signaling center and dental cusps morphogenesis and anomalies -High throughput sequencing 2012 - 2
2012Annick TOUTAINTowersFoundation For Rare DiseasesSpastic paraplegia - glaucoma - intellectual deficitIdentification of the causal gene of a rare syndrome comprising intellectual disability, glaucoma and spastic paraplegia -High throughput sequencing 2012 - 2
2012Bernard GRANDCHAMPParisFoundation For Rare DiseasesMicrocytic anemiaIdentification of causative gene(s) in rare inherited microcytic anemias -High throughput sequencing 2012 - 2
2012Catherine BADENSMarseilleFoundation For Rare DiseasesMetabolic diseaseApplication of high throughput sequencing to the study of patients suffering from metabolic syndrome with an abnormal nuclear cell profile -High throughput sequencing 2012 - 2
2012Delphine HERONParisFoundation For Rare DiseasesIntellectual deficiency syndromeIdentification of the gene involved in a new form of syndromic recessive intellectual deficiency -High throughput sequencing 2012 - 2
2012Franck RUMMELEParisFoundation For Rare DiseasesBowel diseaseGenetic causes of very-early onset inflammatory bowel diseases -High throughput sequencing 2012 - 2
2012Frederic RIEUX-LAUCATParisFoundation For Rare DiseasesSystemic lupus erythematosusIdentification of genetic factors involved in the pathophysiology of early-onset Systemic Lupus Erythematosus -High throughput sequencing 2012 - 2
2012Gaël MANESMontpellierFoundation For Rare DiseasesRetinitis pigmentosaIdentification of novel genes in autosomal dominant retinitis pigmentosa
in three extensively pre-screened large families
-High throughput sequencing 2012 - 2
2012Guy LENAERSMontpellierFoundation For Rare DiseasesAutosomal dominant optic atrophyNew genes for Autosomal Dominant Optic Atrophy -High throughput sequencing 2012 - 2
2012Gwenaelle COLLOD-BEROUDMarseilleFoundation For Rare DiseasesFocal dystoniaIn search of new genes responsible for dystonia -High throughput sequencing 2012 - 2
2012Jocelyn LAPORTEIllkirchFoundation For Rare DiseasesMyopathiesIdentification of novel genes implicated in different myopathies by exome sequencing -High throughput sequencing 2012 - 2
2012Lydie BURGLENParisFoundation For Rare DiseasesCongenital cerebellar ataxiaIdentification of congenital ataxias genes by exome sequencing -High throughput sequencing 2012 - 2
2012Marie-Christine ALESSIMarseilleFoundation For Rare DiseasesMacrothrombocytopeniaIdentify new causes of hereditary Macrothrombocytopenia -High throughput sequencing 2012 - 2
2012Patrick CALLIERDijon Foundation For Rare DiseasesPai syndromeIdentification of the gene for Pai syndrome through complete exome sequencing -High throughput sequencing 2012 - 2
2012Philippe CHEVALIERLyonFoundation For Rare DiseasesFamilial atrial fibrillationIdentification of novel gene responsible of familial atrial fibrillation -High throughput sequencing 2012 - 2
2012Pierre RAYGrenobleFoundation For Rare DiseasesOocyte maturation failureInvestigation of the genetic aetiology of oocyte maturation failure (OMF) by exome sequencing. -High throughput sequencing 2012 - 2
2012Pierre VABRESDijon Foundation For Rare DiseasesSACRAL/PELVIS syndromeIdentification of postzygotic mutations in SACRAL/PELVIS syndrome -High throughput sequencing 2012 - 2
2012Sophie NICOLEParisFoundation For Rare DiseasesHereditary thermosensitive neuropathySearch for the gene responsible for the hereditary neuropathy with thermosensitivity (complementary whole exome) -High throughput sequencing 2012 - 2
2012Stephane DECRAMERToulouseFoundation For Rare DiseasesCongenital hyperechogenic kidneyIdentification of new genes involved in congenital hyperechogenic kidneys -High throughput sequencing 2012 - 2
2012Sylvie ODENTRennesFoundation For Rare DiseasesAmelo-cerebro-hypohidrotic syndrome (Kohlschütter-Tönz syndrome)Whole exome sequencing in Köhlschutter-Tonz syndrome with probable autosomal dominant transmission -High throughput sequencing 2012 - 2
2012Thierry BIENVENUParisFoundation For Rare DiseasesNeonatal epileptic encephalopathiesIdentification of new genes involved in neonatal epileptic encephalopathies associated with Rett-like features -High throughput sequencing 2012 - 2
2012Thierry BRUE
ParisFoundation For Rare DiseasesPituitary hormone deficiencyExome Project In Combined Pituitary Hormone deficiency (EPIC) Study -High throughput sequencing 2012 - 2
2012Veronique PAQUIS-FLUCKINGERNiceFoundation For Rare DiseasesMitochondrial diseasesMitochondrial diseases with multiple respiratory chain deficiency :
Identification of new genes by exome sequencing
-High throughput sequencing 2012 - 2
2013Agnes ROTIGParisFoundation For Rare DiseasesHepatic failure of mitochondrial originTargeted region sequencing in hepatic failure of mitochondrial origin -High throughput sequencing 2013 - 1
2013Alain TAIEBBordeaux Foundation For Rare DiseasesTrichothiodystrophyTFIIH sequencing of a new TTD (trichothiodystrophy) phenotype -High throughput sequencing 2013 - 1
2013Benoit ARVEILERBordeauxFoundation For Rare DiseasesOculocutaneous albinismExome sequencing to find new gene(s) involved in oculocutaneous albinism -High throughput sequencing 2013 - 1
2013Bertrand ISIDORNantesFoundation For Rare DiseasesCamurati-Engelmann diseaseIdentification of the disease causing gene in sporadic and familial forms of Camurati- Engelmann syndrome not linked to TGFB1 -High throughput sequencing 2013 - 1
2013Cecile JULIERParisFoundation For Rare DiseasesJuvenile onset insulin-independent diabetesIdentification of genes responsible for monogenic forms of juvenile onset insulindependent diabetes -High throughput sequencing 2013 - 1
2013Fabienne ESCANDELille Foundation For Rare DiseasesHolt-Oram syndromeIdentification of new genes involved in Holt Oram Syndrome by Exome Sequencing -High throughput sequencing 2013 - 1
2013Helene DOLLFUSStrasbourgFoundation For Rare DiseasesBardet-Biedl syndromeNovel genes identification in Bardet-Biedl Syndrome (BBS) -High throughput sequencing 2013 - 1
2013Mathilde VARRETParisFoundation For Rare DiseasesFamilial hypercholesterolemiaIdentification of new genes involved in rare forms of autosomal dominant hypercholesterolemia
-High throughput sequencing 2013 - 1
2013Pascale DELONLAYParisFoundation For Rare DiseasesRhabdomyolysisIdentification of the gene(s) responsible for recessive rhabdomyolysis in 10 patients from 5 families presenting the same phenotype -High throughput sequencing 2013 - 1
2013Pascale RICHARDParis Foundation For Rare DiseasesInherited cardiomyopathyIdentification of new genes associated with inherited cardiomyopathies. -High throughput sequencing 2013 - 1
2013Patrice BOUVAGNETLyonFoundation For Rare DiseasesTetralogy of FallotTetralogy of Fallot -High throughput sequencing 2013 - 1
2013Richard REDONNantesFoundation For Rare DiseasesArrhythmia syndromes: Early repolarisation syndromeA genetic survey on Early Repolarisation Syndrome -High throughput sequencing 2013 - 1
2013Rima NABBOUTParis Foundation For Rare DiseasesFebrile Induced Refractory Epilepsy in SchoolExome sequencing to identify genes associated with FIRES (Febrile Induced Refractory Epilepsy in School) -High throughput sequencing 2013 - 1
2013Sophie SAUNIERParis
Foundation For Rare DiseasesNephronophthisisIdentification of new genes involved in nephronophthisis -High throughput sequencing 2013 - 1
2013Stephane BEZIEAUNantesFoundation For Rare DiseasesAcrodermatitis enteropathica, zinc deficiency typeWhole-exome sequencing of a cohort of patients with inherited forms of zinc deficiency acrodermatitis enteropathica-like -High throughput sequencing 2013 - 1
2013Alexandra HENRION-CAUDEParisFoundation For Rare DiseasesBiliary atresiaBiliary atresia in consanguineous and familial cases - High throughput sequencing 2013 - 2
2013Annick TOUTAINTowersFoundation For Rare DiseasesX-linked intellectual disabilityIdentification of the causal gene in a family with non-specific X-linked disability - High throughput sequencing 2013 - 2
2013Claude FERECBrestFoundation For Rare DiseasesAutosomal dominant polycystic kidney diseaseSearch for a new locus involved in dominant cystic kidney disease - High throughput sequencing 2013 - 2
2013Claude JARDELParisFoundation For Rare DiseasesMitochondrial diseasesTowards the identification of novel genes involved in mitochondrial functions in genetically and biochemically informative patients - High throughput sequencing 2013 - 2
2013Corinne ANTIGNACParisFoundation For Rare DiseasesIdiopathic steroid-sensitive nephrotic syndromeIdentification of genes involved in autosomal recessive steroid-sensitive nephrotic syndrome (SSNS) - High throughput sequencing 2013 - 2
2013Cyril MIGNOTParisFoundation For Rare DiseasesSepto-optic dysplasiaIdentification of a gene involved in septo optic dysplasia with schizencephaly - High throughput sequencing 2013 - 2
2013Emmanuel FLAMAND-ROZEParis Foundation For Rare DiseasesParoxysmal kinesigenic dyskinesiaIdentification of new genes involved in paroxysmal kinesigenic dyskinesias -High throughput sequencing 2013 - 2
2013Eric PASMANTParisFoundation For Rare DiseasesCarcinoid tumor and carcinoid syndromeExome sequencing for identification of the gene responsible for a rare familial midgut carcinoid tumor syndrome - High throughput sequencing 2013 - 2
2013Federico DI ROCCOParisFoundation For Rare DiseasesFamilial scaphocephaly syndromeExome sequencing of familiar isolated scaphocephalies - High throughput sequencing 2013 - 2
2013Florent SOUBRIERParisFoundation For Rare DiseasesHereditary hemorrhagic telangiectasiaGenetics of hereditary hemorrhagic telangiectasia - High throughput sequencing 2013 - 2
2013Gaetan LESCALyonFoundation For Rare DiseasesWest syndromeIdentification of novel genes involved in West syndrome in ten patients with extensive pre-screening. - High throughput sequencing 2013 - 2
2013Jean-Baptiste RIVIEREDijonFoundation For Rare DiseasesSpondylocostal dysostosisUnraveling the genetic basis of spondylocostal dysostosis - High throughput sequencing 2013 - 2
2013Jean-Jacques SCHOTTNantesFoundation For Rare DiseasesFamilial mitral valve prolapseGenetic analysis of inherited mitral valve prolapse - High throughput sequencing 2013 - 2
2013Laurent VILLARDMarseilleFoundation For Rare DiseasesEarly infantile epileptic encephalopathyIdentifying genetic causes of early infantile epileptic encephalopaties - High throughput sequencing 2013 - 2
2013Mathieu BARBIERParisFoundation For Rare DiseasesFamilial thoracic aortic aneurysm and aortic dissectionIdentification of new gene involved in familial thoracic aortic aneurysm and dissection (FTAAD) - High throughput sequencing 2013 - 2
2013Patricia FERGELOTBordeaux Foundation For Rare DiseasesRubinstein-Taybi syndromeExome study in Rubinstein-Taybi syndrome patients with no alteration in the CREBBP and EP300 genes - High throughput sequencing 2013 - 2
2013Rosa VARGAS POUSSOUParis Foundation For Rare DiseasesDistal renal tubular acidosisIdentification of new gene(s) responsible for recessive distal Renal Tubular Acidosis -High throughput sequencing 2013 - 2
2013Sandrine VUILLAUMIER-BARROTParisFoundation For Rare DiseasesType I congenital disorder of glycosylationExome sequencing of 8 patients with a neurologic form of type I congenital disorder of glycosylation - High throughput sequencing 2013 - 2
2013Severine DRUNATParisFoundation For Rare DiseasesBaraitser-Winter syndromeBaraitser-Winter syndrome - searching causal genes in patients without ACTB/G1 mutations - High throughput sequencing 2013 - 2
2013Stephane VIVILLEIllkirchFoundation For Rare DiseasesPartial chromosome Y deletionGenetics of male infertility: genes implicated in non-obstructive azoospermia - High throughput sequencing 2013 - 2
2013Sylvain LATOURParisFoundation For Rare DiseasesInherited lymphoproliferation syndromesMolecular identification of novel forms of inherited lymphoproliferation syndromes associated with a susceptibility to EBV infection - High throughput sequencing 2013 - 2
2013Valerie CORMIER-DAIREParisFoundation For Rare DiseasesSpondylodysplastic dysplasiaFurther identification of the molecular basis of the spondylodysplastic dysplasias group through the study of 6 families - High throughput sequencing 2013 - 2
2013Veronique PINGAULTCreteilFoundation For Rare DiseasesWaardenburg syndromeIdentifying new genes of Waardenburg syndrome - High throughput sequencing 2013 - 2
2013Christel THAUVIN-ROBINETDijonFoundation For Rare DiseasesRare head and neck malformationsCreation of a mouse model of Cohen's syndrome -Outside AAP
2013Claude BESMONDParisFoundation For Rare DiseasesOther rare diseasesNiNi -Outside AAP
2013Jean-Luc GALZIStrasbourgFoundation For Rare DiseasesImmune deficiency disordersIdentification of CXCL12 neutraligands and CXCR4 antagonists to block WHIM-related gain of signaling function -Outside AAP
2013Laurence LEGEAI-MALLETParisFoundation For Rare DiseasesRare head and neck malformationsCraniofacial anomalies and FGFR3 -Outside AAP
2013Laurent GOUYAParisFoundation For Rare DiseasesHereditary metabolic diseases Treatment of Acute Hepatic and Erythropoietic Porphyria: Search for inhibitors of the regulatory enzymes ALAS1 and ALAS2 -Outside AAP
2013Xavier JEUNEMAITREParisFoundation For Rare DiseasesArterial hypertensionGeneration of CUL3 delta-ex9 mouse model reproducing a mendelian form of arterial hypertension -Mouse models 2013
2013Jeanne AMIELParisFoundation For Rare DiseasesEpiphyseal, vertebral, and ear dysplasiaProposal to create a mouse model of EVE dysplasia by generating Hspa9 knockout mice -Mouse models 2013
2013Delphine DELACOUR ParisFoundation For Rare DiseasesCongenital tufting enteropathyFunctional characterization of Spint2 in intestinal morphogenesis - Physiopathological repercussions in the pathogenesis of CTE - Mouse models 2013
2013Claire FRANCASTELParisFoundation For Rare DiseasesImmunodeficiency, centromeric region instability, facial anomalies syndrome Creation and epigenetic/phenotypic characterization of a mouse model for the ICF type II syndrome -Mouse models 2013
2013Fiona FRANCISParisFoundation For Rare DiseasesHeterotopiaMolecular and cellular causes, and physiopathology of heterotopia -Mouse models 2013
2013Laurent GOUYAParisFoundation For Rare DiseasesErythropoietic protoporphyriaAntisense oligonucleotide therapeutic strategy in EPP: Development of a humanized mouse model. - Mouse models 2013
2013Rima NABBOUTParisFoundation For Rare DiseasesRare epilepsiesKI Mouse model for Migrating partial seizures in infancy -Mouse models 2013
2013Thierry LEVEILLARDParisFoundation For Rare DiseasesRetinitis pigmentosaInactivation of the thioredoxin-like protein RdCVFL encoded by the Nucleoredoxin-like71 gene: RdCVFL7-7 mouse -Mouse models 2013
2013Frederic SAUDOUOrsayFoundation For Rare DiseasesHuntington diseaseHuntington's disease: modelling huntingtin proteolysis in mouse (proteo-htt) - Mouse models 2013
2013Alain HOVNANIANParisFoundation For Rare DiseasesNetherton syndromeDevelopment of a murine model overexpressing human Kallikrein 14 in the context of Netherton syndrome -Mouse models 2013
2013Jean-Jacques MERCADIERChatenay-MalabryFoundation For Rare DiseasesCatecholaminergic polymorphic ventricular tachycardiaAdvances in the understanding and treatment of Catecholamine Polymorphic Ventricular Tachycardia (CPVT) - Mouse models 2013
2013Rima NABBOUT ParisFoundation For Rare DiseasesMalignant migrating partial seizures of infancyKI Mouse model for Migrating partial seizures in infancy -Mouse models 2013
2013Alain LILIENBAUMParisFoundation For Rare DiseasesDesminopathyA mouse model for desmin-related myopathies -Mouse models 2013
2013Luc DUPUISStrasbourgFoundation For Rare DiseasesAmyotrophic lateral sclerosisGeneration of an inducible model of amyotrophic lateral sclerosis through conditional truncation of fus/als - Mouse models 2013
2013Sabine BAILLYGrenobleFoundation For Rare DiseasesHereditary hemorrhagic telangiectasiaBMP10 in HHT disease -Mouse models 2013
2013Antoine MARTINEZClermontFoundation For Rare DiseasesCarney complexPathogenic potential of R1α truncated mutants found in severe forms of Carney complex -Mouse models 2013
2013Marie-Christine CHABOISSIERNiceFoundation For Rare DiseasesDisorders of sex developmentAnalysis of R-spondin1 functions in transdifferentiation and maintenance of the ovary - Mouse models 2013
2013Michaël SEBBAGHMarseilleFoundation For Rare DiseasesPeutz-Jeghers syndromeSTRAD beta involvement in Peutz-Jeghers syndrome -Mouse models 2013
2013Michael MITCHELLMarseilleFoundation For Rare DiseasesPartial chromosome Y deletionRole of the homologue of a human oligozoospermia factor gene, during mouse spermatogenesis -Mouse models 2013
2013Hamid-Reza REZVANIBordeauxFoundation For Rare DiseasesXeroderma pigmentosum complementation group CRole of NADPH oxidase 1 in Xeroderma pigmentosum C - Mouse models 2013
2013Chantal HARDYNantesFoundation For Rare DiseasesSteinert myotonic dystrophySociological approach to lifestyle habits of adults with myotonic dystrophy type 1 Le changement des habitudes de vie des personnes atteintes d’une maladie chronique invalidante est mal connu et pourtant essentiel à prendre en compte pour soigner efficacement dans la durée. La dystrophie myotonique de type1 (DM1 ou maladie de Steinert) est une maladie chronique exemplaire (ou typique) : elle est rare, génétique, évolutive, altère plusieurs fonctions, son traitement est, actuellement, exclusivement symptomatique. La problématique médicale intègre relativement facilement cette diversité clinique dans une prise en charge interdisciplinaire, mais les soins sont caractérisés par un contexte relationnel conflictuel entre soignants et soignés. En effet, ces patients sont souvent décrits comme revendicatifs tout en manifestant un « manque de motivation » dans la gestion de leur maladie.
Le contexte français du développement de l’éducation thérapeutique et les besoins de préventions des complications de la DM1 identifiés par les soignants, font apparaître des besoins pédagogiques qu’il convient d’interroger au regard des représentations sociales, des manières de vivre et des habitudes de vie des personnes atteintes de cette maladie.
Se situant à la croisée des champs médical et social, cette étude vise à comprendre le changement des habitudes de vie au cours des stratégies d’adaptation des hommes et des femmes adultes atteints d’une maladie neuro-dégénérative, la DM1.
La méthode se caractérise d’abord par une approche pluridisciplinaire (sociologique, infirmière et médicale) autour d’un projet commun : mieux comprendre pour mieux soigner. Dans un contexte de reconfigurations régionales, le projet s’appuie sur une approche réellement transdisciplinaire en intégrant une coopération étroite entre une équipe SHS (UMR6297, Droit et changement social) et le Centre de Référence de Maladies Neuromusculaires Rares (CRMNMR) Nantes-Angers. Il s’inscrit en outre dans la démarche de réflexivité soin-recherche engagée au sein du DHU 2020 centré sur la médecine personnalisée des maladies chroniques. Ce projet a pour ambition de poser les bases d’une réflexion sur une vision davantage compréhensive que normative de la maladie permettant à l’ensemble des acteurs de s’approprier les résultats susceptibles d’enrichir et de modifier les pratiques. Pour y parvenir, un groupe de pilotage, composé des deux équipes de recherche, complété de représentants des usagers et de la recherche fondamentale, sera sollicité aux étapes cruciales du projet.
La méthodologie de cette étude s’appuie sur le modèle conceptuel de développement humain et de processus de production du handicap (MDH-PPH) développé au Québec, complété de l’étude des dispositions incorporées par les individus au cours de leur vie les conduisant à un hexis particulier. Les données seront collectées à l’aide d’outils relevant de la sociologie et de l’anthropologie (analyse de dossiers de patients, observations de séances d’hôpital de jour, entretiens et observations de patients à domicile, entretiens avec des soignants). Elles seront analysées selon la méthodologie de la théorie ancrée afin de modéliser les interactions entre la personnalité, l’environnement et les habitudes de vie de notre population. L’échantillon d’au moins 20 personnes atteintes de DM1 dont les manifestations cliniques sont apparues après l’âge de 20 ans est issu en priorité de la file active du CRMNR Nantes-Angers. Une première étude de cette population montre des caractéristiques médicales, cognitives, sociales et culturelles compatibles avec les objectifs de l’étude.
L’approche originale de cette étude devrait produire une description précise des caractéristiques de la population, des déterminants qui influencent l’adaptation à la vie quotidienne, une compréhension approfondie des interactions entre les différents acteurs et une modélisation du changement des habitudes de vie. Ces connaissances scientifiques seront largement communiquées et publiées pour permettre aux professionnels du soin et aidants à domicile de préciser, voire de modifier leurs pratiques de soins et de prévention, d’adopter la posture la plus respectueuse et efficace pour accompagner, dans la durée, cette population à définir ses propres normes et l’accompagner dans l’accomplissement de son projet de vie. Les formateurs, les concepteurs d’actions de prévention et d’éducation thérapeutique pourront s’appuyer sur ces nouvelles données pour enrichir leurs programmes.
En rompant avec une approche souvent normative des déterminants sociaux de santé, habituellement utilisés dans les travaux sur les inégalités sociales de santé, cette étude propose ainsi une approche inductive prenant en compte les interactions entre soignants et soignés et la diversité des habitudes de vie.
Humanities and Social Sciences 1
2013Federico DI ROCCOParisFoundation For Rare DiseasesCraniosynostosisCraniosynostosis: how to improve the announcement of the diagnosis and support patients and their families? Context: this project is part of a collaborative effort involving social science researchers, a medical team and neuropsychologists from a reference center for patients with craniostenosis, and a dedicated patient association. Craniostenosis is a primitive growth abnormality of the cranial skeleton associated with premature closure of one or more cranial sutures. These malformations - some forms of which are genetic in origin - have morphological as well as functional implications: cranial and facial dysmorphia with psychological consequences in terms of relationships with others, and a potentially degraded self-image; but also a growth conflict between cranium and brain, which can lead to cerebral compression, mental retardation, learning difficulties and visual disturbances. Treatment is surgical. It aims to correct the deformation of the cranial skeleton, while normalizing intracranial pressure and helping to prevent complications.
The moment of the announcement in the Reference Center is crucial because of the impact it has on the child himself, on the parents' view of their child and on the view of others (siblings, educational team, carers, etc.), as well as on the place of the dysmorphic child within the family scheme.

Aims: to improve diagnosis and management:
1. better understand the experience of the announcement for patients and their families
2. improve understanding of the announcement and its appropriation according to the patient's age
3. identify intra-family issues surrounding the announcement of a genetic mutation
4. reconstruct the patient's care pathway by analyzing the consequences of the announcement time.

Methods :
In order to achieve the objectives of this research project, it was deemed appropriate to use a combination of quantitative and qualitative methods, combining a desire for an exhaustive approach with the consideration of subjective elements during the announcement. This research will favour a longitudinal perspective.
The methodological tools to be developed are interview guides, questionnaires and observation reports.
For the qualitative part, complementary analyses of two types will be carried out: a thematic content analysis of the verbatims, and an interpretative analysis aimed at reconstructing the subjects' journeys, avoiding the division caused by the thematic analysis.
For the quantitative part, cross-tabulation will be used.

Expected results:
A typology of the forms of announcement will highlight the issues linked to the specificities of the disease, such as the announcement of the genetic mutation, and will enable improvements to be made in this area, as well as in the management and support of parents.
Oral presentations will be given at the study day organized by the Centre de Référence des dysostoses cranio-faciales, at the annual Patients' Association day, at the Craniofacial Surgery congress and at social science symposia. The presentations will focus on research findings and present the specificities of the care pathway for these patients, particularly with regard to the announcement phase.
Dissemination within the scientific community is envisaged through two publications in international peer-reviewed scientific journals.

Impact of the project:
This research will help to identify the specific features of the announcement phase and of patient support by taking into account the diversity of patient pathways, by analyzing patient pathways.
The originality of this research lies in the interdisciplinarity of the teams involved, and the cross-fertilization of perspectives from the different professional fields involved.
The aim of this research is to provide medical teams and patients with a better understanding of the announcement process and the support provided to patients and their families, with a view to improving the announcement protocol. It will also provide an inventory of the current situation, a prerequisite for drawing up part of a national plan for the diagnosis and care of craniostenosis.
Humanities and Social Sciences 1
2013Herve CHAMBOSTMarseilleFoundation For Rare DiseasesHaemorrhagic diseasesInput of a multidisciplinary management approach in announcing the diagnosis for young children with serious constitutional haemorrhagic diseases and their families Severe hemophilia and associated severe forms of constitutional hemorrhagic disease (CHD) expose patients to recurrent joint and muscle bleeding, which is a major factor in the functional prognosis of these conditions. Although modern therapies have radically transformed these patients' life expectancy and orthopedic status, the occurrence of complications such as cerebral hemorrhage or the development of an inhibitory antibody can significantly alter the prognosis.
The announcement of the diagnosis of these rare pathologies, which usually occurs in an infant, represents a definite trauma. Changes in the psychological functioning of children with hemophilia and their parents have been described. The evidence of psychomotor development disorders in these children points to the impact of hyperprotective behavior on the part of the parents, which can be identified as soon as the diagnosis is announced.
The development of preventive therapeutic approaches using long-term prophylactic substitution (LDP) aims to improve orthopedic functional prognosis by reducing spontaneous joint bleeding. However, the success of such prophylaxis can be hampered by a number of factors, of which poor compliance is an important one.
At the hemophilia treatment center, we have developed a multi-disciplinary support system to accompany the announcement of the diagnosis, focusing on a psychological approach and reassurance, with the aim of facilitating psychomotor development, improving quality of life and encouraging acceptance of early prophylaxis. This program, which includes a variety of actions (individual psychological interviews, discussion groups, "Chemin faisant" workshop, therapeutic education program), is set up very early on after the announcement and is carried out in conjunction with the Association Française des Hémophiles (French Hemophilia Association), which offers complementary actions, notably within the framework of its family commission.
In this context, we propose to set up a monocentric, descriptive, cross-sectional pilot study for around 30 children aged 2 to 10, suffering from hemophilia or associated HCM and cared for at the Marseille CRTH as soon as they are diagnosed. For these children, who have therefore been able to benefit from all or part of the diagnostic announcement support system over the past 10 years, the aims of our study are as follows:
1/ Primary objective: to study adherence to prophylaxis recommendations and quantify compliance with treatment, in relation to participation in the scheme offered by the CTH.
2/ Secondary objectives: 2a/ to compare adherence results for the Marseille CTH patient population with those analyzed in other centers (data from a PHRC currently underway); 2b/ to describe the psycho-affective state of the patient and his or her entourage (parents), as well as their appropriation of the disease, in our model of care which favors the intervention of a psychologist; 2c/ to describe the quality of life of this population.
The tools used for this research will include
- Analysis of PLD compliance data (N days of prophylaxis and treatment regimen)
- Clinical assessment, based on the number of joint bleeds over a period of time and an orthopedic score
- Psychological and psychopathological assessment through detailed tests
- A detailed study of quality of life, using questionnaires adapted to the evaluation of children's QOL by themselves and/or by their parents according to age, but also studying the parents' QOL.
This type of single-center study will be a prerequisite for larger-scale studies, to determine the real impact of making this type of organization available in pediatric HTCs. This study, and any others that may follow, will provide a basis for discussion of the possibility of allocating budgets specifically for this type of care in other centers, as described and implemented in our center.
Humanities and Social Sciences 1
2013Maria TEIXEIRAParisFoundation For Rare DiseasesSickle cell disease - Cystic fibrosisTransition and insertion in the adult world of young people with sickle cells disease or cystic fibrosis Contexte : La drépanocytose est une maladie autosomique récessive. Cette pathologie se caractérise par une modification de la forme des globules rouges qui entraîne une anémie dite anémie falciforme et des douleurs chroniques aiguës, de graves infections bactériennes et des nécroses. Cette maladie atteint surtout les populations d’Afrique, de certaines régions méditerranéennes, du Moyen-Orient et d’Asie. Chaque année, en France métropolitaine et dans les Dom Tom environ 400 nouveau-nés viennent au monde avec un syndrome drépanocytaires clinique majeur dont 250 à 270 en Ile-de-France. Cette pathologie nécessite une prise en charge médicale qui s’étend de l’enfance à l’âge adulte. Celle-ci implique que les jeunes passent d’une prise en charge pédiatrique à une prise en charge adulte par un processus de transition or celui-ci pose des problèmes ayant des conséquences sur leur qualité de vie médicale et sociale.
Objectifs : Notre perspective de recherche est constituée de deux axes. D’une part, nous évaluerons rétrospectivement la transition de la médecine pédiatrique vers la médecine adulte et d’autre part nous analyserons l’impact de cette transition sur la socialisation des jeunes atteints de drépanocytose. Nous évaluerons les réussites et les échecs du dispositif mis en place à l’hôpital Robert Debré par les Dr Benkerrou et Lionnet pour accompagner la transition de la médecine pédiatrique vers la médecine adulte. En effet, certains jeunes parviennent à s’insérer au monde médical et social adulte, mais d’autres n’y parviennent pas, sont perdus de vue et d’un point de vue sanitaire mettent leur santé et parfois leur vie en danger. Aussi nous nous interrogerons sur l’impact de la réussite ou de l’échec de cette transition sur l’insertion sociale de ces jeunes. Nous nous attacherons à l’analyse des dimensions somatiques et des expressions sociales des émotions. Nous étudierons les représentations sociales de la douleur et de la maladie, les représentations du corps individuel et du corps familial et la place de ces jeunes malades au sein de leur famille. Nous analyserons l’impact de ces représentations et de cette place sur le vécu des maux et l’insertion sociale, qu’elle soit scolaire, professionnelle, affective ou médicale. Une problématique en termes d’origine géographique devra également être conduite puisque la drépanocytose associe le stigmate de la maladie à celui des origines et de la migration.
Méthodes : Notre approche méthodologique est pluridisciplinaire. Nous associons ici à la fois des thérapeutes et des professionnels des dimensions sociales de la maladie. Seront réalisés :
• 24 entretiens individuels avec des jeunes de 18 à 25 ans dont la transition en médecine adulte est effective. Parmi ces 24 jeunes, 12 auront réussi leur transition et 12 seront en rupture de suivi. Les entretiens se dérouleront au domicile des patients.
• 24 entretiens individuels ou en groupe avec les membres de la famille présents au domicile le jour de l’entretien avec le jeune.
• Des entretiens avec les professionnels de santé qui ont suivi les jeunes jusqu’à leur transition et qui connaissent l’histoire clinique des patients.
Au sein des entretiens, nous identifierons les thématiques qui émergent et les récurrences. Chaque entretien fera l’objet d’un portrait résumé récapitulatif et problématisé qui rend compte de manière synthétique de l’expérience singulière de chaque interviewé. Nous observerons les conditions de vie des patients et de leur famille. Nous consignerons sur un carnet de terrain les discours informels. Les matériaux recueillis (entretiens) et élaborés (portraits résumé, notes de terrain) seront organisés dans le logiciel Nvivo10.
Résultats attendus et impact : Cette étude nous permettra de recueillir des données : (1) sur les représentations de la douleur, de la maladie et le vécu de la transition du point de vue des jeunes et de leur famille, (2) afin d’évaluer rétrospectivement l’efficacité de l’accompagnement entre médecine pédiatrique et médecine adulte. (3) Ainsi nous améliorerons la qualité de cette transition pour qu’elle ait un impact positif sur les stratégies développées par les patients pour s’insérer au niveau scolaire, professionnel, affectif ou médical. (4) Ceci nous permettra de mettre en place une meilleure prise en charge des difficultés psychologiques spécifiques rencontrées par les jeunes atteints de drépanocytose. (5) Par cette recherche nous contribuerons à l’identification des différents mécanismes sociaux qui favorisent les discriminations. Ainsi nous pourrons les déconstruire et les révéler.
Pertinence du projet au regard de l’état des connaissances : Peu de recherches sur les dimensions sociales et culturelles du vécu de la drépanocytose existent en France et une seule recherche sur la transition de la médecine pédiatrique vers la médecine adulte dans cette pathologie est en cours. Aucune évaluation de cette transition n’a pu encore être effectuée ni l’impact d’une réussite ou d’un échec de cette transition sur l’insertion sociale des jeunes.
Humanities and Social Sciences 1
2013Melanie JACQUOTStrasbourgFoundation For Rare DiseasesNeuromuscular diseaseClinical and psychopathological approach of neuromuscular disease on gender identityThe onset of a rare neuromuscular disease leads to limitations in bodily performance. Yet sexual identity, as the feeling of recognizing oneself and being recognized as belonging to a gender, directly involves the body, in its performative and relational dimension.
While the question of sexuality in disabled people is currently the subject of a great deal of research, we propose an original approach that shifts sexual identity away from genital sexuality and inscribes it in an intersubjective dimension. Current psychological research on sexual identity reveals that it remains dependent on the gaze of others, and particularly subject to the events that punctuate the subject's life, such as the onset of illness.

Using a qualitative methodology (semi-structured interview, projective tests) and a quantitative one (questionnaires on quality of life, depression, anxiety and family functioning), this research aims to assess the effects of the onset of a neuromuscular disease on sexual identity as it is understood in its relational dimensions: love, family and work.
In addition, we wish to explore the impact of family economy, professional maintenance and the relationship with caregivers in the reorganization and rearrangement of sexual identity specific to rare neuromuscular diseases.

The aim of this descriptive research is to identify concrete actions to be developed in the context of the psychological care of patients, and in particular :
- identify possible risks of psychopathological decompensation (particularly the presence of depressive elements)
- identify family dynamics and the support provided by parents and siblings
- train and support those involved in the patient's professional integration
- assess the need for psychological support.

The proposed descriptions of the psychological impact of rare neuromuscular diseases, and the avenues for action identified in relation to career paths and the organization of care, could be used to benefit descriptions of other rare diseases.
Humanities and Social Sciences 1
2013Pascal JOLYRouenFoundation For Rare DiseasesPemphigusIdentification of vulnerability factors in the course of pemphigus patients Context: The etiological diagnosis of rare diseases with developmental anomalies is still too often unknown, leading to medical wandering, prolonged diagnostic searches and incomprehension on the part of families. Moreover, this represents a potential loss of opportunity for access to appropriate genetic counseling, optimal follow-up and possible therapeutic resources. The dynamic progress observed over the last two years in terms of technological innovation points to a veritable revolution in diagnosis, research and treatment for patients. Following on from the diagnostic discoveries made possible by the widespread use of DNA chips, high throughput sequencing (HTS) is set to transform the field of developmental pathologies considerably, from basic research to care. However, before transferring this technology into daily practice, particularly for exome HDS diagnostic expertise, we need to be able to anticipate the information that needs to be communicated to patients and parents in order to consent to exome HDS, and the questions raised in terms of diagnostic announcement (uncertain results, incidental results of chance discovery). These questions go beyond the use of technology, and represent a real societal challenge, requiring the involvement of teams from the human and social sciences, in particular psychologists, sociologists and ethicists, to ensure that patients suffering from rare diseases can benefit from innovative technologies under optimum conditions of information and support.

This project is the initiative of 2 Maladies Rares Anomalies du Développement et Syndromes Malformatifs reference centers, which have joined forces with teams from the Human and Social Sciences at the University of Burgundy, the "Ethics and Medical Progress" research team led by the Espace de Réflexion Ethique Bourgogne/Franche-Comté within Inserm CIT 808 at the Besançon CHRU, and patient associations.

Objectives: The aim of this project is to develop the modalities and content of the information to be provided to parents and prescribing physicians in order to consent to the performance of an HHS. The aim is to anticipate clinical practices in terms of prescribing, diagnosis and support for patients/families.

Methodology: The project will be carried out in three phases:
1/ Qualitative study among parents, prescribing physicians and geneticists who will announce the results, concerning their expectations, representations and issues linked to the arrival of high-speed sequencing. Individual interviews will be conducted using human and social science methods, by a researcher trained in clinical and qualitative research.

2/ Collection, from the 8 French FeCLAD centers and European reference centers, of information and consent documents and procedures currently in use.

3/ Design by a multidisciplinary group of the methods and content of the information to be given to doctors and parents, based on the results of the qualitative study, the documents collected and the synthesis of the relevant literature. Definition by this group of a protocol for evaluating the implementation of the selected information actions.

Expected results and impact: This will have repercussions in terms of anticipating the announcement, training doctors, setting up appropriate support for families, providing a basis for reflection on the drafting of consents at national level, and discussing how to improve the organization of care, particularly in delicate situations.
Relevance of the project to the current state of knowledge: In the absence of national regulations governing the use of this technology, it is necessary for groups to initiate discussions on the information to be communicated, in order to anticipate the arrival of HDS as a diagnostic tool in daily practice. The teams involved in this call for projects have already begun to think about this issue, and have operational teams in their laboratories who can rapidly implement these techniques, and therefore feel the need to be able to answer the questions posed.
Humanities and Social Sciences 1
2013Philippe ALLAINAngers Foundation For Rare DiseasesHuntington diseaseBehavioural disorders in Huntington's disease: Analysis and valorisation of the expertise of the patients and their caregivers Contexte.
La maladie de Huntington (MH) est une maladie neurodégénérative rare se manifestant par des symptômes moteurs, cognitifs, psychiatriques et/ou comportementaux. Il s’agit d’une maladie génétique, autosomique dominante à pénétrance complète; cela signifie que le risque de transmission pour un sujet atteint est de 50% et qu’un sujet porteur d’un allèle muté développera inéluctablement la maladie. La MH débute le plus souvent entre 30 et 45 ans, sans prédominance de sexe ni d’ethnie. L’ordre d’apparition des symptômes varie d’un patient à l’autre, mais ceux-ci conduisent inéluctablement à une démence par dégénérescence des circuits neuronaux striato-frontaux. Les personnes atteintes de MH et leurs proches rencontrent des restrictions importantes dans leur participation à la vie en société. Ces restrictions sont souvent secondaires aux troubles cognitifs, psychiatriques et aux modifications comportementales accompagnant la maladie. La situation des personnes atteintes de MH peut être analysée dans le cadre d’un modèle social du handicap, en analysant les déterminants de l’environnement, et notamment les comportements des proches, comme des facilitateurs ou des obstacles à leur participation sociale.
Objectifs et rationnel
L’objectif du travail vise à recueillir, décrire et analyser le corpus de connaissances des proches sur les troubles du comportement accompagnant la MH et de le transcrire dans deux registres : un registre théorique et un registre pratique. Le registre théorique visera à élaborer une typologie des interactions conduisant au processus de production du handicap. Le registre pratique se voudra plus pragmatique et formatif. Nous pensons en effet que le traitement des troubles du comportement dans la maladie de Huntington relève pour partie d’une adaptation de l’environnement relationnel du patient. A partir des données recueillies dans cet environnement relationnel et de leur formalisation théorique, nous pensons pouvoir développer un module de formation, destiné aux familles et aux professionnels, notamment du secteur médico-social, qui permettront la transmission de cette expertise d’usage.
Il s’agira d’une étude transversale descriptive monocentrique. Une double approche quantitative et qualitative sera utilisée. La méthodologie employée consistera en un recueil de données quantitatives et une analyse qualitative fondée sur des entretiens semi-directifs de malades et de proches. La population étudiée comprendra 80 patients avec MH avérée (stades 1 et 2) et leurs proches, vivant à domicile. Le recrutement s’appuiera sur les usagers du Centre National de Référence pour les Maladies Neurogénétiques et de l'Adulte d’Angers (Coordonateurs : Pr D. Bonneau, généticien, Pr C. Verny, neurologue). Les évaluations quantitatives reposeront sur les outils utilisés dans le Centre (l'Unified Huntington's Disease Rating Scale qui évalue les facultés dans les domaines moteur, cognitif, comportemental et fonctionnel, une échelle évaluant les signes et symptômes de la dépression et de l’affaiblissement émotionnel, un auto-questionnaire des signes suggérant la dépression, une échelle du risque suicidaire, une échelle de qualité de vie, une échelle mesurant l’impact socio-économique de la MH et des problèmes de santé liés à la MH, une échelle permettant de rendre compte de l’influence d’un sujet porteur de la mutation de la MH / ou personne à risque sur la cellule familiale et l’environnement social). Nous y ajouterons des épreuves neuropsychologiques permettant d’évaluer les aptitudes à la base des conduites sociales (empathie, perception des émotions, théorie de l’esprit affective et cognitive) ainsi qu’un questionnaire ciblant les troubles comportementaux liés au syndrome dysexécutif. Les variables qualitatives recueillies seront basées sur 40 entretiens semi-directifs de « couples » patient MH-proche. Une analyse de contenu thématique sera réalisée, a posteriori. Elle portera sur le retentissement des troubles dans la vie quotidienne, la fréquence des troubles, leur évolutivité, la limitation éventuelle de la participation sociale, les attitudes aggravant ou diminuant les troubles, les adaptations mises en place par les proches. Cette analyse de contenu s’appuiera sur la méthode par catégorisation de mots et de thèmes récurrents émergeant dans les discours des sujets.
Résultats attendus, impact et pertinence du projet. Les résultats quantitatifs attendus sont l’évaluation de l’importance et de la fréquence des troubles du comportement accompagnant la MH, des variables neuropsychologiques susceptibles d’en rendre compte et de leur retentissement sur la participation sociale. Les résultats qualitatifs attendus sont la description des interactions personne/environnement et de la typologie des situations aggravant ou palliant les troubles comportementaux, la description des connaissances et représentations des proches. Cette étude aura un impact sur les personnes inclues et fera l’objet d’une large diffusion par communications et publications scientifiques et par la création d’un module de formation.
Humanities and Social Sciences 1
2013Philippe METELLUS / David TAIEB MarseilleFoundation For Rare DiseasesVon Hippel-Lindau diseasePsychosocial consequences of screening for Von Hippel-Lindau disease in patients operated for an hemangioblastoma of the central nervous system BACKGROUND: Von Hippel Lindau syndrome (VHL) is a serious, under-diagnosed, autosomal dominant inherited disorder predisposing to numerous tumors, some of which are malignant, such as clear-cell carcinoma, which is a major prognostic factor in this condition.
CNS hemangioblastoma (HB) is one of the conditions currently recommended for VHL screening. Screening of affected subjects would enable us to diagnose around 20% of VHL subjects, and thus to detect other conditions at an early stage, since this is chronologically the 2nd condition to occur during the course of VHL.
This approach poses a number of problems. Indeed, the announcement of a potentially serious disease is delicate, and there is inevitably a psychosocial impact linked to the family dimension of the disease.
OBJECTIVES: The primary objective of this study is to assess the impact in terms of anxiety of genetic screening for VHL gene mutations in patients with CNS hemangioblastoma operated on in the neurosurgery department of La Timone from 1999 onwards, by comparing patients who are ultimately considered to be non-mutated with those in whom the mutation has been identified.
Secondary objectives are to assess the impact of screening on various other pyschosocial parameters for these two groups, and the prevalence of other VHL-related conditions in mutated patients.
This study will be carried out in conjunction with the PREDIR reference center and the VHL France association.
METHOD: The primary endpoint is anxiety. Anxiety will be assessed by means of the Anxiety Trait Inventory (STAI).
Secondary evaluation criteria:
Depressive symptoms will be assessed using the Beck scale.
Quality of life will be measured using a generic questionnaire: the SF36.
Psychological consequences of screening will be assessed using the Psychological Consequences Questionnaire.
These parameters will be assessed before the genetic screening is carried out and after the results are returned,
Close follow-up by a psychologist will be offered to all patients.
EXPECTED RESULTS AND IMPACT: 42 distinct patients were identified from the neurosurgery registry of the Timone department, based on data from the anatomopathology department.
After consulting the molecular biology software of Pr Barlier at CHU Conception, 6 patients have already been identified (including 2 mutated patients). There are therefore 36 potential patients to be included, to whom we can add 5 potential new patients during the course of the study (number extrapolated from the number of HB cases operated on per year in the neurosurgery department), giving a total of 41 patients. We hope to obtain an 80% response to our letter, i.e. 33 patients.
The expected proportion of mutated patients is 30%, i.e. 10 mutated and 23 non-mutated patients.
This number of subjects, 10 cases for 23 controls, will enable us to highlight a 12-point difference in anxiety levels, with a standard deviation of 10, a power of 80% and an alpha risk of 5%.
PROJECT RELEVANCE: Our approach is also prospective, with the introduction of systematic screening for new cases of hemangioblastoma.
In view of the ongoing discovery of new cancer-causing genes, this model study will enable us to better assess the psychosocial impact of genetic screening, and thus better manage it in everyday medical practice.
Humanities and Social Sciences 1
2013Severine COLINET - Laurence HEIDETGennevilliersFoundation For Rare DiseasesRenal fetal pathologyAnnouncement of a severe renal fetal pathology detected during pregnancy Background: Severe kidney disease diagnosed before birth can result in severe renal failure early in life. The prognosis is often uncertain. Faced with this situation, parents are faced with the dramatic choice of whether or not to carry out a medical termination of pregnancy (Engelmann, 2002). While this choice is guided by psychological, ethical, cultural and religious considerations specific to each individual, it is obviously also largely determined by what the doctor tells them, and in particular by the way in which they are presented with their child's kidney disease. The doctor finds himself in an individually difficult position, confronted as he is with his own questions, anxieties and representations. The announcement is by its very nature singular, and therefore differs from one practitioner to another. It is essential to reflect on the determinants of the announcement, the content of the discourse, and how it is perceived by future parents. The aim of this study is to provide a basis for this reflection by analyzing doctor-parent interviews and the way they are perceived by each party. To this end, the project will involve social science researchers and medical teams from three renal disease reference centers (Paris-Necker, Lyon, Grand Ouest) that regularly perform antenatal diagnosis, in conjunction with the Centres Pluridisciplinaires de Diagnostic Pré Natal (CPDPN).

The project will be led by social science researchers, with a university professor and a senior lecturer. They will coordinate the work of a post-doctoral social scientist. At each of the three sites, from the very first month, the teams will be made up of members of the reference centers and CPDPNs: pediatric nephrologists, obstetricians, geneticists, radiologists, psychologists and/or child psychiatrists. A referent will be proposed for each center.

Objectives: Stimulate collective reflection on practices for announcing and presenting information on renal disease before birth, in order to improve the announcement to couples and their management as part of their care pathway. Over a 14-month period, we propose to:
1) draw up an inventory and analysis of announcement practices.
2) analyze the way in which patients perceive, hear and integrate the announcement, and the impact of this announcement on the parents' decision concerning the unborn child, whether to terminate or continue the pregnancy. In this case, the aim is to analyze the impact on the representation of the unborn baby, the parent(s)-child bond, the child-fraternity bond and the future of the family structure (couples, siblings).

The methodological tools to be developed are semi-structured interview guides, questionnaires and observation reports.
Quantitative and qualitative surveys will be carried out in each of the three centers.

Retrospective quantitative survey
300 questionnaires will be distributed and sent out to all couples who have visited the three renal disease reference centers (Paris, Lyon, Grand Ouest) over the past three years.
Variables will be analyzed using multiple correspondence sorting.

Prospective qualitative survey
Patients and their spouses (when present): 15. These subjects will be interviewed twice, at different times: 6 months and 1 year after the announcement. A total of 30 interviews will be conducted. At the same time, 10 interviews will be conducted with doctors, and observations will be made during consultations with the nephrologist and obstetrician, as well as with the psychologist or child psychiatrist.
As for the qualitative part, two types of complementary analysis will be carried out: a thematic content analysis of the verbatims, and an interpretative analysis designed to avoid the division caused by the thematic analysis.
Humanities and Social Sciences 1
2013Virginie POSTALBordeauxFoundation For Rare DiseasesPrader-Willi syndromeAssessment of the impact of cognitive, executive and emotional abilities on the difficulties of adaptation and socialization of patients with PWSPrader-Willi syndrome (PWS) is a rare genetic disorder (incidence 1/15,000 to 1/25,000, Whittington et al., 2007) described in 1956 (Prader, Labhart&Willi, 1956). It is a neurodevelopmental disorder of genetic origin linked to the absence of gene expression in the 15q11-q13 region of chromosome 15 of paternal origin (parental genomic imprinting). This is an extremely complex disease, due to the diversity and severity of the disorders involved. There are major difficulties in managing the disease, partly due to behavioral disorders that are often linked to difficulties in understanding and adapting to the individual's environment, present from childhood onwards (sociable but unsocializable individuals -Dr. Thuilleaux). At birth, there is major hypotonia (enabling early diagnosis) associated with sucking and eating disorders, followed by the rapid and early onset of obesity with hyperphagia and satiety deficit, leading in the absence of prevention and treatment to the development of extremely severe morbid obesity (Goldstone et al. 2008). There are also endocrine disorders, with multiple hypothalamic-pituitary hormone deficiencies (Diene et al. 2010). Various behavioral disorders are associated with the syndrome: obsessive-compulsive disorders, temper tantrums, stubbornness, a tendency to steal and lie, plus learning and communication difficulties. Patients have a lower IQ than the general population, with a normal distribution around an average of 60 and variations according to genetic origin (Copet et al., 2010).
While behavioral descriptions and recommendations in terms of diagnosis and medical management are currently relatively well supported (cf. Protocole national de diagnostic et de soinspour les maladies rares, HAS, 2012), the identification of specific cognitive and emotional disorders and their impact on individuals' day-to-day adaptation are very poorly understood. Socialization difficulties become very prevalent in adulthood, with over 50% of adults remaining in their families without occupation. The presence of an intellectual deficit and executive dysfunction specific to the syndrome means that life plans need to be adapted to this population, which is rarely the case at present.
The aim of this project is to describe abilities (cognitive, executive, emotional and social adjustment) at different ages of life, in order to propose adjustments to life projects from childhood to adulthood, both in medical and social care, and in everyday life via families. The knowledge acquired will enable us to develop an information tool for care providers.
Firstly, various neuropsychological tests will be administered to assess general cognitive and executive functioning in relation to emotional components (also in relation to food) in PWS patients followed up at the Toulouse and Hendaye reference centers (60 children and adolescents and 60 adults). In a second phase, we will compare the results of the research with the experience and observations of families "in real-life situations" (lay experts) and a group of experts from the reference center. This work will make it possible to implement the theoretical side of the best practice guide currently being drafted, and to produce an information medium for training meetings at the competence centers, with a longer-term evaluation. The project will involve the sites of the PWS Reference Center, the Prader-Willi France association, the 22 competence centers and the University of Bordeaux.
Humanities and Social Sciences 1
2014Fabrice LEJEUNELilleFoundation For Rare DiseasesDuchenne Muscular DystrophyCorrection of nonsense mutations in genetic diseases10% of patients suffering from a genetic disease are carriers of a STOP mutation responsible for the pathology. STOP mutations lead to the premature cessation of protein synthesis from the mutant gene. We are looking for chemical molecules that can induce the cellular machinery to ignore the presence of the mutation and thus lead to complete protein synthesis. To identify these molecules, we have built a biological system capable of testing thousands of molecules in order to select those with the property of correcting STOP mutations. The project presented here proposes to use a platform equipped with devices capable of testing tens of thousands of molecules in a matter of days, in order to accelerate the discovery of new molecules and increase the chances of identifying future drugs for patients suffering from a genetic disease.
High-throughput screening 2013
2014Damien SANLAVILLELyonFoundation For Rare DiseasesIntellectual disability / congenital malformationsStudy of 9 complex chromosomal rearrangements by massively parallel sequencing: an unifying mechanism? -High throughput sequencing 2014 - 1
2014Florent SOUBRIERParisFoundation For Rare DiseasesIgA nephropathy (Berger's disease)Exome sequencing in two large pedigrees with multiple cases of IgA nephropathy - High throughput sequencing 2014 - 1
2014Giovanni STEVANINParisFoundation For Rare DiseasesHereditary spastic paraplegiaWhole genome sequencing in 5 families with hereditary spastic paraplegia -High throughput sequencing 2014 - 1
2014Jean-Louis MANDELIllkirchFoundation For Rare DiseasesIntellectual disability/autismExome sequencing of patients with intellectual disability and no mutation identified in known genes -High throughput sequencing 2014 - 1
2014Karine POIRIERParisFoundation For Rare DiseasesMicrolissencephalyIdentification of new genes involved in microlissencephaly -High throughput sequencing 2014 - 1
2014Marion GERARDCaenFoundation For Rare DiseasesSirenomelia / mermaid syndromeWhole-exome sequencing to identify genetic alterations associated with Sirenomelia (ADEP project) -High throughput sequencing 2014 - 1
2014Nadia BAHI-BUISSONParisFoundation For Rare DiseasesAicardi syndromeIdentification of the genetic bases of Aicardi syndrome -High throughput sequencing 2014 - 1
2014Pascale GUICHENEYParisFoundation For Rare DiseasesIdiopathic ventricular fibrillation with short-coupled variant of torsade de pointesIdentification of a new gene causing idiopathic ventricular fibrillation with short-coupled variant of torsade de pointes -High throughput sequencing 2014 - 1
2014Patrick CALLIERDijonFoundation For Rare DiseasesFrontonasal dysplasiaGenetic basis of frontonasal dysplasia -High throughput sequencing 2014 - 1
2014Patrick REVYParisFoundation For Rare DiseasesSevere bone marrow failure, dyskeratosis congenita, Hoyeraal-Hreidarsson syndromeIdentification of new genes involved in severe bone marrow failure associated with telomere and/or dna repair defects -High throughput sequencing 2014 - 1
2014Sandrine VUILLAUMIERParisFoundation For Rare DiseasesGlut1 deficiencyIdentification of a gene underlying dominant epilepsy in a slc2a1/glut1 negative family (trio analysis) -High throughput sequencing 2014 - 1
2014Sophie NICOLEParisFoundation For Rare DiseasesPeriodic paralysisSearch for a new gene responsible for periodic paralysis by whole exome analysis of one family and sporadic cases -High throughput sequencing 2014 - 1
2014Valerie CORMIER-DAIREParisFoundation For Rare DiseasesEllis-Van Creveld syndromeIdentification of the molecular basis of the Ellis-Van Creveld (EVC) syndrome -High throughput sequencing 2014 - 1
2014Valerie DELAGUEMarseilleFoundation For Rare DiseasesCharcot-Marie-Tooth diseaseIdentification of novel genes in Charcot-Marie-Tooth disease in lebanese consanguineous families, through homozygous by descent analysis of whole genome sequence data -High throughput sequencing 2014 - 1
2014Veronique PAQUIS-FLUCKINGERNiceFoundation For Rare DiseasesMitochondrial diseases Early-onset neuromuscular presentations of mitochondrial disorders: identification of new genes by exome sequencing -High throughput sequencing 2014 - 1
2014Aude MAGERUS-CHATINETParisFoundation For Rare DiseasesAutoimmune lymphoproliferative syndrome (ALPS)Search for modifier genes in ALPS-Fas -High throughput sequencing 2014 - 2
2014Carine LE GOFFParisFoundation For Rare DiseasesFloating Harbor syndromeIdentification of a new gene involved in Floating Harbor syndrome -High throughput sequencing 2014 - 2
2014Christel DEPIENNEParisFoundation For Rare Diseasesautism-epilepsyIdentification of novel genes responsible for autism-epilepsy phenotypes -High throughput sequencing 2014 - 2
2014Eric BIETHToulouseFoundation For Rare DiseasesCongenital bilateral absence of the vas deferens (CBAVD)Search for new genetic determinants of male infertility due to congenital bilateral absence of the vas deferens -High throughput sequencing 2014 - 2
2014Francis COUTURAUDBrestFoundation For Rare DiseasesIdiopathic venous thromboembolismidentification of new inherited thrombophilia in selected families - High throughput sequencing 2014 - 2
2014Gaël MANESMontpellierFoundation For Rare DiseasesAutosomal dominant retinitis pigmentosaIdentification of novel genes in autosomal dominant Retinitis Pigmentosa in 21 fully screened families for known genes -High throughput sequencing 2014 - 2
2014Gaëlle HARDYGrenobleFoundation For Rare DiseasesHereditary bradykinin-mediated angioedemaNews genes involved in bradykinin-mediated angioedema with reduced C1-inhibitor function and no mutation in SERPING1 or F12 genes -High throughput sequencing 2014 - 2
2014Irene NETCHINEParisFoundation For Rare DiseasesRussell-Silver SyndromeIdentifying new genes responsible for autosomal inheritance of Russell-Silver syndrome -High throughput sequencing 2014 - 2
2014Jamal GHOUMIDLilleFoundation For Rare DiseasesBlepharo-cheilo-dontic (BCD) syndromeMolecular characterization of blepharocheilodontic (BCD) syndrome through exome sequencing in 5 families -High throughput sequencing 2014 - 2
2014Michel POLAKParisFoundation For Rare DiseasesCongenital hypothyroidismIdentification of new genes involved in brain-lung-thyroid syndrome -High throughput sequencing 2014 - 2
2014Nadia BAHI-BUISSONParisFoundation For Rare DiseasesCortical Malformations and 22q11.2 deletion syndromeDelineation of the molecular basis of cortical malformation in 22q11.2 deletion syndrome -High throughput sequencing 2014 - 2
2014Reiner VEITIAParisFoundation For Rare DiseasesPrimary Ovarian InsufficiencyGenetics and Genomics of primary ovarian insufficiency: an entry point to understand ovarian function -High throughput sequencing 2014 - 2
2014Rolando MELONIParisFoundation For Rare Diseasesfamilial form of bipolar disorderResearch of a major gene for familial form of bipolar disorder in an extended pedigree with an ascertained founder effect. -High throughput sequencing 2014 - 2
2014Sebastien MOUTTONBordeauxFoundation For Rare DiseasesOEIS (omphalocele - exstrophy of bladder - imerforate anus - spinal defects) complexIdentification of the molecular bases of OEIS complex in a multiplex family -High throughput sequencing 2014 - 2
2014Thomas FALGUIÈRESParisFoundation For Rare DiseasesRare hepatobiliary diseasesIdentification of targeting correctors of ABCB4/MDR3 defective mutants by a high throughput screening approachBile secretion is an essential function of the liver, playing a detoxifying role and helping to digest dietary fats. One of the compounds in bile, phosphatidylcholine, is secreted through the action of a protein called ABCB4, located on the surface of hepatocytes, the cells of the liver. However, adult and pediatric patients suffering from rare biliary pathologies have mutations in ABCB4, preventing it from reaching the cell surface correctly. Current treatments are not very effective in treating the most severe forms of these diseases, including PFIC3 (progressive familial intrahepatic cholestasis type 3), which affects very young children, with liver transplantation remaining the only alternative for more than half of them. We propose to identify new compounds capable of effectively treating these patients. To achieve this, a high-throughput screening approach will be used: using a robotized system, several thousand compounds will be tested for their ability to restore ABCB4 addressing in a cellular model mimicking the pathological situation.High-throughput screening 2013
2014Irene CEBALLOS-PICOTParisFoundation For Rare DiseasesLesch-Nyhan DiseaseIdentify molecules able to induce HPRT-like activity in HPRT-deficient fibroblasts and dopaminergic neuronal cells as models for Lesch-Nyhan Disease Lesch-Nyhan disease (LND) is a rare neurometabolic disorder caused by a deficiency of an enzyme in the purine recycling pathway, hypoxanthine-guanine phosphoribosyltransferase (HPRT). This very severe clinical syndrome combines hyperuricemia, severe dystonia (uncontrollable muscle contractions leading to abnormal, incoordinated movements) and behavioral disorders leading to very severe, compulsive self-mutilation. The HPRT enzyme deficiency is caused by mutations in the HPRT gene, but the pathophysiological mechanisms leading to neurobehavioral disorders remain unclear. In addition to the classic LND form, there is a less severe form of the disease, known as Lesch_Nyhan Variants (LNV). These LNV patients present with hyperuricemia and variable neuromuscular abnormalities, but NO self-mutilation. Mutations in the HPRT gene in LNVs reduce enzymatic activity, and residual HPRT activity (10%) is generally sufficient to prevent major neuromuscular problems.
Our aim is therefore to try to restore residual HPRT activity, thereby reducing major neuromuscular and neurobehavioral disorders in LND patients, by screening molecules on a large scale in patients' epidermal cells (fibroblasts). A chemical library (Prestwick) containing 1,200 molecules will be screened using a simple viability test (yes/no). Selected molecules will then be validated for their ability to restore HPRT-like activity on fibroblasts from LND patients. The use of a chemical library made up of molecules already approved for medical use (French marketing authorization) will enable rapid testing of candidate molecules in patients.
High-throughput screening 2013
2014Delphine MEYNARDToulouseFoundation For Rare DiseasesNon-transfusion-dependent thalassemiaMatriptase-2: identification of pharmacological inhibitors to decrease iron overload in non-transfusion-dependent thalassemiaThalassemias are hereditary diseases of hemoglobin, the substance in red blood cells that carries oxygen throughout the body. To survive, patients must receive red blood cells by transfusion. Among thalassemias, a small group of patients can survive without transfusion. However, because of the reduced number of red blood cells, these patients have a major iron overload in the liver. This iron overload is dangerous, as it leads to fibrosis, cirrhosis and liver cancer.
As current treatments are not optimal (side effects, cost), we propose to develop a new therapy for these patients based on matriptase-2. Matriptase-2 is a protein which, when inhibited, blocks the entry of iron into the body. In this project, we will screen for small molecules inhibiting matriptase-2 which, when administered to patients, could correct their iron overload and prevent associated pathologies. What's more, this treatment can be administered to patients in pill form, and will be inexpensive.
High-throughput screening 2013
2014Olfa KHALFALLAHNiceFoundation For Rare DiseasesFragile X syndromeSearch for active molecules on a cell model for Fragile X Syndrome by high throughput screeningFragile X syndrome (FXS) is the most common form of hereditary mental retardation (1/5500), and results from mutation of the FMR1 (Fragile X Mental Retardation 1) gene, and consequent absence of the FMRP protein. In the absence of this protein, communication between neurons is defective. At present, there is still no treatment for FXS. This is because the FMRP protein is important not only for communication between neurons, but also for the formation of these neurons themselves. This latter aspect has been little studied, and constitutes my research project.
I have developed a cellular model mimicking the pathology, which has enabled us to better understand how the absence of FMRP alters neuron formation, and that it is possible to pharmacologically correct these alterations. Thus, our model has a twofold interest:
- to determine when the absence of FMRP triggers the disease, so as to identify new therapeutic windows
- to test pharmacological molecules already available on the market in order to find new, better-adapted therapies and improve the quality of life of FXS children.
High-throughput screening 2013
2014Fabrice LEJEUNEParisFoundation For Rare DiseasesAll nonsense mutation-related diseasesCORRECTION OF NONSENSE MUTATIONS IN GENETIC DISEASES10% of patients suffering from a genetic disease are carriers of a STOP mutation responsible for the pathology. STOP mutations lead to the premature cessation of protein synthesis from the mutant gene. We are looking for chemical molecules that can induce the cellular machinery to ignore the presence of the mutation and thus lead to complete protein synthesis. To identify these molecules, we have built a biological system capable of testing thousands of molecules in order to select those with the property of correcting STOP mutations. The project presented here proposes to use a platform equipped with devices capable of testing tens of thousands of molecules in a matter of days, in order to accelerate the discovery of new molecules and increase the chances of identifying future drugs for patients suffering from a genetic disease.
High-throughput screening 2013
2014Hanna DEBIEC ParisFoundation For Rare DiseasesMembranous nephropathySearching for C5b-9 antagonists by high-throughput screening of chemical libraries: Toward new treatment of membranous nephropathyThe aim of our project is to identify new drugs active in extramembranous glomerulopathies, which are kidney diseases caused by antibodies most often directed against the cells of the kidney filters known as glomeruli. When these filters are altered, the result is a massive leakage of albumin into the urine, leading to edema (swelling of the legs) and eventually renal failure. Today, we have immunosuppressive treatments that inhibit antibody production, but their effects are delayed. These antibodies are responsible for activating complement, which attacks cell membranes and induces urinary leakage of albumin. We will use a robotic system to identify new molecules that inhibit complement activation in cell cultures from libraries of potential drugs. In this way, we hope to develop rapidly effective drugs that can be used in other autoimmune diseases such as lupus.High-throughput screening 2013
2014Marie-Anne COLLENantesFoundation For Rare DiseasesPompe Disease (glycogenosis of type II)Gene therapy for pediatric forms of Pompe disease using AAV gene transfer to the CNS: preclinical feasibility in nonhuman primatePompe disease is a progressive genetic disorder caused by a deficiency of the enzyme acid alpha-glucosidase, which breaks down glycogen in cells. Glycogen accumulates in the muscles and heart, leading to locomotor, respiratory and cardiac disorders, which in the most severe form are fatal within the first year of life. Current treatment by intravenous delivery of the missing enzyme has corrected the heart and increased patients' life expectancy, but has revealed damage to the central nervous system. Thanks to our gene therapy treatment, which uses a viral vector to deliver the enzyme into the cerebrospinal fluid, we have been able to treat the nervous system of mice suffering from the disease. Before we can consider applying this treatment to humans, we need to evaluate its efficacy and safety in an animal with a brain size and organization more similar to our own: the non-human primate.Preclinical research 2014
2014Philippe MOULLIERNantesFoundation For Rare DiseasesDuchenne muscular dystrophySystemic injection in the GRMD dog of a recombinant AAV vector encoding for the µdystrophin: efficiency and global safetyThe aim of this project is to evaluate a "whole body" gene therapy treatment in dogs with spontaneous Duchenne muscular dystrophy. Not only are we aiming to target the heart and diaphragm, but also the skeletal muscles, in order to deliver a truly global therapeutic benefit. In this respect, the availability and familiarity of the canine model of this disease is a definite advantage in determining the therapeutic dose of our drug. One of the strengths of this project is that we have very encouraging preliminary results for one of our products, which clearly provided a therapeutic benefit in our first 3 dogs injected via a simple intravenous route. The second strength of our project is that all this work is being carried out by a consortium that is unique in the world, in which we have brought together experts in gene vectors, molecular biologists, anatomical pathologists, physiologists, veterinarians, scientists and doctors. This consortium, which has been working together since 2009, is already involved in an exon skipping clinical trial which will shortly be submitted to the French drug agency.Preclinical research 2014
2014Pierre-Louis THARAUXParisFoundation For Rare DiseasesRapidly progressive glomerulonephritis (RPGN)Treatment of rapidly progressive glomerulonephritis by powerful inhibitors of HB-EGF and miRNA92a pathway in pigRapidly progressive glomerulonephritis (RPGN) is an orphan disease linked to an anarchic proliferation of the cells forming the kidney's filtration units. Current treatments are ineffective and very costly, and kidney loss is frequent. The disease is due to overproduction of the growth factor HB-EGF in response to autoantibody deposits in the kidney. Pierre-Louis Tharaux, nephrologist at Georges Pompidou Hospital, has demonstrated that blocking HB-EGF prevents the development of the disease. He has also identified a cellular substance, micro-RNA92a, implicated in the disease. The research project involves reproducing the disease in pigs, and testing as a treatment a therapeutic protein developed at the CEA by Daniel Gillet's team, as well as a micro-RNA92a blocker developed at Inserm U970 at Georges Pompidou Hospital. The experiments will be conducted with the help of INRA at Jouy-en-Josas.Preclinical research 2014
2014Sibylle OPSAHL-VITALMontrougeFoundation For Rare DiseasesX-linked hypophosophatemic ricketsDevelopment of a bioengineering treatment for the necrotic pulp of patients with familial rickets: preclinical approach in the mini-pigPatients with hypophosphatemic rickets are prone to spontaneous dental abscesses. These infections are due to structural abnormalities in the tooth, a consequence of the rickets. The usual treatment is devitalization, which weakens the tooth and deprives it of its nerve sensitivity.
Based on the presence of stem cells in the tooth, we aim to offer an alternative to this treatment, by replacing the diseased tissue with artificial pulp, made up of pulp stem cells seeded in a collagen matrix. The regeneration of a new, innervated and vascularized pulp tissue will enable the pulp to maintain its functions of nutrition and sensitivity, guaranteeing the longevity of a functional tooth on the arch.
We have already validated this innovative therapy in rats, and before moving on to humans, it is essential to test it in minipigs, which are closer to human physiology.
Preclinical research 2014
2014Arnaud MONTEILMontpellierFoundation For Rare DiseasesInfantile neuroaxonal dystrophy (INAD)Modeling infantile neuroaxonal dystrophy, a nalcn channel-related disorder, in zebrafishOur ability to identify the genetic origin of certain neurological diseases continues to expand. Such is the case with Infantile Neuroaxonal Dystrophy (INAD), which has just been linked to a "loss-of-function" mutation in a NALCN ion channel. Our aim is to understand the link between this mutation and the mechanisms responsible for the pathology, which requires the development of an animal model. The mouse is not always the model of choice in which this mutation could be lethal. We have therefore chosen, on the basis of our preliminary studies, to study the mutation responsible for INAD using the zebrafish. We will introduce this mutation into the zebrafish genome and perform a series of molecular, biochemical and functional tests on the mutated zebrafish during its development from larva to adult. The zebrafish is a vertebrate with great similarities to humans, enabling us to study the mechanisms of pathologies. The advantage of this model is also that it enables research into drugs that can treat symptoms: drugs that may one day be able to cure INAD patients.Small animal models 2014
2014Dimitrios SKOUFIASGrenobleFoundation For Rare DiseasesMicrocephaly-Lymphedema-Chorioretinal Dysplasia human rare syndromeGeneration of a zebrafish model to study KIF11 motor protein mutations associated with the human MLDRC rare syndromeSmall animal models are used to understand the pathogenic nature of genetic mutations identified in humans that are associated with rare diseases. They can also be used to screen orphan drugs for rare diseases. Recently, mutations in the mitotic motor protein Eg5, encoded by the KIF11 gene, have been linked to autosomal dominant transmission of the rare human syndrome Microcephaly-Lymphoedema-Chorioretinal Dysplasia. However, to date, there is no evidence that the mutations identified in the KIF11 gene are pathogenic. Therefore, we propose the development of a zebrafish model to study the cause and effect of the identified Eg5 mutations in order to elucidate the pathogenic nature of the identified mutations and understand the roles of Eg5 in the development of nervous tissues (e.g. brain, retina) and the lymphatic system affected by the syndrome.Small animal models 2014
2014Frederic PERROSLe Plessis RobinsonFoundation For Rare DiseasesPulmonary arterial hypertensionRole of KCNK3 in the pathogenesis of pulmonary arterial hypertensionPulmonary arterial hypertension (PAH), a rare and incurable disease, is characterized by obstruction of the pulmonary arteries, leading to right heart failure and death. Recently, mutations in the KCNK3 gene have been implicated in the development of PAH.
Unlike the mouse, the rat is an excellent model of cardiovascular disease, and of PAH in particular. However, until recently, the absence of reliable tools for transgenesis in this species has prevented the creation of genetically modified rat models.
The 'Small animal models and rare diseases' call for projects will enable us to generate rats invalidated (KO) for KCNK3, thanks to the TRIP-Nantes platform.
We believe that KCNK3 KO rats will spontaneously develop PAH, providing a relevant model for the human disease.
Many molecules successfully tested in current iatrogenic models of PAH have proved disappointing in humans. We believe that this model, which has a similar etiology to human PAH, will be a better screen for the identification of new PAH therapies.
Small animal models 2014
2014Gregoire MICHAUXRennesFoundation For Rare DiseasesMicrovillus inclusion diseaseTowards a model for rare intestinal absorption diseases in c. elegansSeveral rare diseases, such as microvillous inclusion disease or epithelial dysplasia of the intestine, affect intestinal absorption by preventing intestinal cells from absorbing food; these pathologies most often occur from birth and have a major impact on children's development. Patients receive total parenteral nutrition, i.e. their entire diet is supplied intravenously.
To better understand how these pathologies arise, we propose to use the small roundworm C elegans. The main advantage of this well-characterized model organism is an intestine which, although very simple, has an absorption surface on a cellular scale identical to that found in humans, and is directly accessible by conventional microscopy methods. This makes it possible to characterize absorption defects in vivo, and then seek to compensate for them in order to identify new therapeutic avenues.
Small animal models 2014
2014Herve TRICOIREParisFoundation For Rare DiseasesFriedreich ataxiaGeneration of new endogenous drosophila models of trinucleotide repeat expansion diseasesTriplet expansion diseases are rare and incurable. The creation of new animal models is essential to better understand the mechanisms involved in these diseases. To this end, we aim to develop new Drosophila fly models of 3 of these diseases: Huntington's disease, spinocerebellar ataxia type 2 and Friedreich's ataxia. In recent years, the Drosophila has established itself as an excellent model for genetic studies, as well as for testing compounds for therapeutic purposes.
The new Drosophila models we intend to develop will be based on the integration of a pathogenic triplet repeat in the Drosophila gene corresponding to the human gene involved in the disease. These models, developed in collaboration with TEFOR infrastructure platforms, will more closely resemble what happens in humans and mimic pathologies better than existing models. They will then be studied by our research team, enabling us to develop new therapeutic approaches.
Small animal models 2014
2014Isabelle RICHARDEvryFoundation For Rare DiseasesLimb-girdle muscular dystrophy type 2A Rat model for calpainopathiesSarcoglycanopathies belong to the limb-girdle muscular dystrophies, myopathies grouped on the basis of common clinical features: predominant involvement of the proximal limb muscles. They are progressively disabling, leading to loss of the ability to walk. No curative treatment is currently available. They are caused by mutations in one of the 4 genes coding for sarcoglycans.
We have developed a therapeutic strategy based on the use of molecules that modify the quality control of proteins within the cell, enabling even mutated sarcoglycans to take their place in the membrane of muscle fibers.
Our promising results must now be validated in a suitable animal model, which our mouse model reproducing a human mutation does not allow us to do. Indeed, protein quality control must be different in mice and humans. We would therefore like to build a rat model for sarcoglycanopathies, in order to test our therapeutic approaches in a model more closely resembling humans.
Small animal models 2014
2014Jamile HAZANParisFoundation For Rare DiseasesHereditary Spastic Paraplegia (HSP)Dangerous liaisons: the link between spastin, atlastin and BMP signaling in the pathogenesis of hereditary spastic paraplegiaOur team is seeking to understand how motor neuron axons in the medulla are guided to specific muscle targets in vertebrates. We approach this problem by exploring the consequences of a malfunction in these motor circuits, via the study of genes responsible for hereditary spastic paraplegia (HSP) during zebrafish embryonic development. HSP encompasses a heterogeneous group of rare neurodegenerative diseases characterized by progressive stiffness of the legs, leading to severe walking difficulties. Among the genes responsible for PSH, the genes encoding atlastin and spastin are frequently incriminated in this group of diseases. We have shown that both atlastin and the two isoforms of spastin control, in their own way, the axonal growth of spinal motor neurons and hence the mobility of larvae. Our project now consists in exploring the cellular and molecular defects resulting from the loss of function of these proteins, through the phenotypic analysis of zebrafish mutants of each of these proteins.Small animal models 2014
2014Jocelyn LAPORTEIllkirchFoundation For Rare DiseasesCongenital myopathies and dystrophies, limb girdle muscular dystrophiesValidation and pathophysiological characterization of novel genes for myopathies (MYO-fish)Genetic myopathies lead to severe chronic disability, representing a major burden for patients, their families and our health service. A third of patients have no genetic diagnosis, and there are no specific therapies.
Our objectives are to identify and validate the genes responsible for myopathies and to better understand the pathological mechanisms in order to provide patients with an accurate diagnosis and potential treatments. Thanks to a major sequencing project funded in part by the Fondation Maladies Rares, we have identified new genes involved in several myopathies.
We now propose to validate in zebrafish the importance of these genes for muscle function, and to generate animal models to study pathological mechanisms and enable the testing of chemical compounds that improve these diseases.
Small animal models 2014
2014Kathrin GIESELERVilleurbanneFoundation For Rare DiseasesMuscular dystrophiesDevelopment of C. elegans models for human muscular dystrophiesMuscular dystrophies are rare diseases characterized by progressive loss of muscle, particularly skeletal muscle, but also cardiac and respiratory muscle. To date, over 72 forms of muscular dystrophy and 46 different associated genes are known. Taken together, these diseases affect a significant number of patients, but today there are no effective treatments for them.
Our team uses a small nematode worm to study human muscular dystrophies. In this project, we propose to create various new nematode models of these diseases and include them in a large-scale study aimed at better understanding the mechanisms of muscle degeneration and proposing new avenues for the development of treatments for muscular dystrophies.
Small animal models 2014
2014Nicolas CHARLET-BERGUERANDIllkirchFoundation For Rare DiseasesAmyotrophic lateral sclerosis & frontotemporal dementiaA rat model of amyotrophic lateral sclerosis & frontotemporal dementiaAmyotrophic lateral sclerosis (ALS), also known as Charcot's disease, is a devastating neurodegenerative disorder. It is characterized by the death of motor neurons in the spinal cord, leading to progressive and fatal paralysis. Recently, it has been shown that the most common cause of ALS mutation is a GGGGCC nucleotide repeat expansion in the C9ORF72 gene. However, despite the importance of the C9ORF72 gene, its function is still unknown.
Our preliminary data show that the function of C9ORF72 is to participate in the elimination of protein aggregates toxic to neurons (autophagy). These data are important because they suggest that loss of C9ORF72 function may be involved in neurodegeneration in ALS patients. We would therefore like to obtain funding from the Foundation for Rare Diseases to establish an animal model (KO rat) of this disease.
In conclusion, this project will lead to a better understanding of the causes of ALS, an essential step towards establishing therapeutic strategies.
Small animal models 2014
2014Olivier LOREALRennesFoundation For Rare DiseasesHereditary aceruloplasminemiaHereditary aceruloplasminemia: mechanisms involved in the expression of the disease and development of new therapeutic approaches.Hereditary aceruloplasminemia, linked to a mutation in the ceruloplasmin gene, is a rare genetic disease that manifests itself in adulthood. It is characterized by the development of atypical iron overload, particularly affecting the liver and brain. It is responsible for major neurological syndromes that severely impair quality of life and shorten life expectancy. Treatment does not satisfactorily remove excess iron from the brain, and the prognosis remains severe.
The development of an animal model of aceruloplasminemia in rats will enable us to characterize the disease, gain a better understanding of the mechanisms at both systemic and cerebral levels, and develop innovative therapeutic approaches. A better understanding of this rare disease will also lead to a better understanding of the alterations in cerebral iron metabolism frequently encountered in neurodegenerative diseases.
Small animal models 2014
2014Sophie NICOLEParisFoundation For Rare DiseasesMuscle channelopathies, congenital myasthenic syndromesNeuromuscular excitability disorders in zebrafish: progressive muscle weakness in periodic paralysis and congenital myasthenia.Despite important advances, a major remaining clinical concern in diseases with abnormal neuromuscular excitability is the progressive permanent disability that develops over time. Vacuolar myopathy can occur in hypokalemic periodic paralysis resulting from dominant missense mutations in voltage-sensitive calcium and sodium channels, and muscle atrophy in a recessive form of congenital myasthenia with agrin mutations. Determining the origin of these events and identifying an appropriate treatment requires the use of animal models. We propose to model these two pathologies in zebrafish through constitutional modification of its genome. We will study the phenotype, motor behavior, morphology and neuromuscular physiology of the mutants obtained. We will determine the effect of currently available treatments on the evolution of the disease in adult fish. We then hope to use these animals to identify new compounds against the development of these progressive phenotypes, thus opening up new therapeutic avenues for these orphan diseases which are disabling for everyday life.Small animal models 2014
2014Thomas PIETRIParisFoundation For Rare DiseasesRett syndromeCharacterization of a zebrafish model of Rett syndromeRett syndrome is a rare neurodevelopmental disorder caused by mutations in the MECP2 gene. The syndrome is characterized by a rapid regression of cognitive and motor functions, after apparently normal development. In order to understand the role of MECP2, several mouse models carrying different mutations in this gene were created. These models have revealed numerous alterations in the functioning of the central nervous system, but have not yet enabled us to understand all the functions of MECP2. We therefore intend to create a new model of Rett syndrome, in another vertebrate model, the zebrafish, to gain a better understanding of the functions of this gene. In addition, the zebrafish is a model of choice for high-throughput drug screening, due to its small size and high progeny number. In the future, we hope to be able to use this model for drug screening.Small animal models 2014
2014Veronique MORELLyonFoundation For Rare DiseasesEmery Dreifuss Muscular Dystrophy
Autosomal recessive Cerebellar ataxia Beauce type (ARCA1)
Direct access to Nesprin1 variants contribution to Emery Dreifuss Muscular Dystrophy and Autosomal Recessive Cerebellar Ataxia ARCA1Emery Dreifuss Muscular Dystrophy (EDMD) and Autosomal Recessive Cerebellar Ataxia of Beauce (ARCA1) are both associated with mutations in the Nesprin1 gene. Several different proteins, or variants, are produced from Nesprin1. It has been proposed that muscles or neurons do not express the same Nesprin1 variants. This hypothesis helps to explain how the same gene is associated with muscular or neuronal pathologies: a mutation in the Nesprin1 gene, depending on whether it affects a neuronal or muscular variant, would thus result in a different pathology.
We propose to test this hypothesis using the Drosophila fly as a model animal. We have shown that when the Drosophila Nesprin1 gene is mutated in muscles or neurons, the fly displays motor deficits reminiscent of the symptoms associated with Emery Dreifuss muscular dystrophy or ARCA1 Autosomal Recessive Cerebellar Ataxia.
Small animal models 2014
2014Vincent BERINGUEJouy-en-JosasFoundation For Rare DiseasesPrion diseasesZebrafish model of prion diseasePrion diseases are a group of rare neurodegenerative disorders affecting humans and animals. The conversion of a host protein, the cellular prion protein PrPC, into an abnormally folded and aggregated form, PrPSc, is a key element in the pathogenesis of these diseases.
In humans, prion diseases can be sporadic, genetic or infectious in nature. In all cases, the conformational change of PrPC is involved. A major public health challenge is to gain a better understanding of the neurodegenerative mechanisms involved in the pathogenesis of these diseases, leading to the irreversible death of affected individuals. To this end, we aim to develop a zebrafish model transgenic for mammalian prion proteins that develops prion-like neurodegeneration, either spontaneously or after experimental infection with mammalian prions. The zebrafish has the unique advantage of being able to visualize in situ, and potentially in real time, the phenomena that take place at cellular and molecular level.
Small animal models 2014
2014Yann HERAULTIllkirchFoundation For Rare Diseases16p11.2 microdeletion syndromeA rat model for the 16p11.2 microdeletion syndrome to better understand and treat the cognitive and metabolic disorders induced in humanDeletion of a region of around 600 kb on the short arm of human chromosome 16 is associated with intellectual deficit and obesity. In addition, some patients show autism-like disorders. This deletion is observed with an estimated prevalence of 1-5 in 10,000 in the general population. Mouse models have been designed and show cognitive deficits. They are now being used to test therapeutic approaches to restore normal function.
Here, we aim to develop a rat model of the proximal 16p11 deletion. We will use a combination of technologies combining CrispR/Cas9 and Cre to create the deletion of the homologous region in the rat, well conserved in terms of gene content and orientation. Next, we will use the rat model to characterize phenotypes using standardized functional analyses, in order to compare changes between human patients, mice and rats. Our aim is to analyze the pathophysiology of 16p11 deletion and validate a treatment in these two preclinical model species.
Small animal models 2014
2014Yvon TROTTIERIllkirchFoundation For Rare DiseasesSpinoCerebellar Ataxia 7 (SCA7)A zebrafish model of SCA7 for physiopathological analyses and drug evaluationSpinocerebellar ataxia 7 (SCA7) is a rare disease causing impaired vision and ataxia. The disease is caused by a mutation that confers neurotoxic properties on a protein called ataxin-7. We have recently discovered that this toxicity affects the function of the cilium, a multifunctional cellular organelle, and that affected neurons progressively lose their characteristic features, leading to death. However, the exact mechanisms of toxicity remain to be elucidated.
Our project aims to study these mechanisms in a zebrafish model, to complement and assist our studies already undertaken in mice. On the other hand, we aim to use this model to make an initial assessment of drugs that could have beneficial effects on the disease, before undertaking more costly and time-consuming studies in mice.
Small animal models 2014
2014Herve DEVILLIERSDijonFoundation For Rare DiseasesSystemic lupus erythematosus / Systemic sclerosis / Inflammatory myopathy Impact of autoimmune disease on quality of life: a qualitative studyContexte
Le Lupus Erythémateux Systémique (LES), la sclérodermie systémique (Ssc) et les myopathies inflammatoires (MI) sont des maladies rares, dont la prévalence est estimée respectivement à 43, 15 et 10 cas pour 100 000 habitants en France. Ces pathologies appartiennent au groupe des maladies auto-immunes et nécessitent un suivi spécialisé par un centre expert. Le retentissement du LES, de la Ssc et des MI sur la vie quotidienne des patients est lourd et lié notamment à l’atteinte cutanée, aux diminutions des capacités fonctionnelles et à leur retentissement psychologique. Ces pathologies concernant dans l’immense majorité des situations des individus d’âge moyen, le retentissement socio-professionnel est majeur et trop souvent négligé.
Les conséquences de la maladie en termes de qualité de vie pour ces patients sont habituellement approchées par des questionnaires, génériques ou spécifiques. La plupart de ces outils a fait l’objet d’une évaluation psychométrique quantitative. Cependant, aucun questionnaire ne permet d’approcher exhaustivement les problématiques de ces patients.
Objectifs principaux :
- Définir les concepts associés au retentissement du LES, de la Ssc et des MI sur la vie quotidienne des patients.
- Analyser l’expérience de la maladie du point de vue du malade
- Analyser les conséquences de la maladie sur la vie quotidienne des patients : vie conjugale et familiale,
vie professionnelle, vie sociale, relations médecin-patient, etc.
- Faire apparaître d’éventuelles différences selon certaines caractéristiques socio-démographiques (sexe,
âge, situation familiale, catégorie sociale), économiques et selon le type de maladies.
- Faire émerger des problématiques méconnues des soignants ou non explorées par les instruments
actuellement utilisés en routine pour évaluer la qualité de vie.
Objectif secondaire :
- Formuler des items, à partir des données qualitatives, dans la perspective de la constitution ultérieure d'une banque d'items.
L’étude repose sur une approche sociologique et a recours aux méthodes qui lui sont propres.
1) Après un inventaire exhaustif des instruments d’évaluation de qualité de vie et de santé perceptuelle utilisés au cours du LES, de la Ssc, et des MI, un groupe de travail sera constitué pour chacune des 3 pathologies autour d’un sociologue, de patients et des médecins spécialistes de la pathologie concernée au sein d’un centre de référence labellisé. A partir de l’expérience du groupe de travail et des données de la littérature, une grille d’entretien semi-directif sera élaborée pour chacune des 3 pathologies
2) A l’issue de cette phase, un sociologue sera intégré à l’équipe de 3 services de référence (2 services de
médecine interne de la Pitié Salpêtrière et service de Médecine Interne du CHU de Lille) et d’un centre de compétence (Service de Médecine Interne du CHU de Dijon) pendant un an. Des entretiens semi- directifs seront réalisés avec des patients jusqu’à saturation des concepts d’intérêt, ce qui nécessite habituellement une trentaine de patients. Chaque entretien sera enregistré et retranscrit par un sociologue expérimenté sous la direction du laboratoire de sociologie de l’université de Dijon pour dégager l’ensemble des dimensions de la vie des patients impactées par les pathologies.
3) Les entretiens feront l’objet d’une analyse de contenu thématique pour déterminer les éléments de la vie des patients qui leur pose problème et qui sont les plus difficiles à supporter.
4) Les différents aspects soulevés par l’analyse thématique seront ensuite formulés sous forme d’items par chacun des 3 groupes de travail, et comparés aux dimensions explorées par les échelles habituellement utilisées.
5) Le contenu de ces items sera ensuite discuté par des focus groupe qui seront constitué pour chacune des trois pathologies
Résultats attendus et impacts
- Identification des aspects du retentissement de la maladie sur la qualité de vie non pris en compte par les soignants et les instruments actuellement utilisés en routine
- Ouverture possible sur la constitution d’une banque d’item exhaustive comprenant les items des échelles existantes complétés par les items formulés à l’issue des problématiques identifiées par cette étude
Pertinence au regard de l’état des connaissances :
Peu d’études ont porté sur le retentissement spécifique de ces pathologies sur la vie quotidienne des patients à
l’aide d’une approche qualitative. Actuellement, l’évaluation du retentissement qualitatif de ces pathologies est
peu réalisée en pratique clinique quotidienne par des spécialistes et l’identification de problématiques non
habituellement prises en compte par les soignants nous permettraient d’améliorer la prise en charge globale des
Humanities and Social Sciences 2
2014Alexandre EUSEBIOMarseilleFoundation For Rare DiseasesProgressive supranuclear palsyQuality of life and caregiver burden in progressive supranuclear palsyContexte : La paralysie supranucléaire progressive (PSP) est une affection neurodégénérative rare faisant partie du groupe des syndromes parkinsoniens atypiques. Elle représente environ 5 à 10% des syndromes parkinsoniens avec un nombre de malades estimé entre 3000 et 10000 en France.
La PSP est caractérisée cliniquement par l’association d’un syndrome parkinsonien non-dopasensible à prédominance axiale avec instabilité à la marche et chutes précoces, de troubles oculomoteurs à type de limitation dans la verticalité du regard et de troubles cognitivo-comportementaux se manifestant essentiellement par un ralentissement psychique, une apathie et un syndrome frontal dysexécutif. S’y associent également des troubles de la déglutition qui peuvent entrainer des complications mettant en jeu le pronostic vital (pneumopathies d’inhalation). Actuellement la prise en charge est exclusivement symptomatique faute de traitement curatif disponible. Dans ce contexte thérapeutique limité et compte tenu de ses caractéristiques cliniques, la PSP impacte considérablement la qualité de vie des patients et également de leur entourage naturel impliqué dans leur prise en charge. Pourtant peu d’études documentent précisément ces deux aspects. Mieux connaitre les déterminants de la qualité de vie de ces individus et de leur entourage peut permettre d’optimiser les prises en charge.
Objectifs: L’objectif principal de cette étude est d’identifier les déterminants (moteurs, psycho- comportementaux, socioéconomiques, environnementaux...) de la qualité de vie patients PSP
Les objectifs secondaires sont: i) d’identifier les déterminants (médicaux, socioéconomiques, comportementaux, environnementaux...) de la qualité de vie et du fardeau des aidants de patients PSP ; ii) réaliser la validation linguistique française de l’échelle de qualité de vie disponible en anglais (PSP-QoL).
Méthodes : Une étude transversale multidisciplinaire sera mise en place dans le centre de compétence maladies rares du mouvement et de la cognition de Marseille (Services de Neurologie des Pr Azulay et Ceccaldi, APHM) en collaboration avec Orphandev (Structure affiliée à l’INSERM spécialisée dans l’étude des maladies rares), des structures de recherche dans le champ des sciences humaines et sociales (Equipe Qualité de vie et maladies Chroniques ; Laboratoire de Psychologie sociale de la santé, Aix Marseille Université et l’Unité d’aide Méthodologique à la recherche clinique (APHM).
Population d’étude : 2 groupes de sujets seront inclus : i) sujets PSP ; ii) sujets aidant d’un patient PSP (désigné par le patient comme la personne la plus proche de lui),
Données recueillies : i) auprès du patient : données sociodémographiques, relatives à l’environnement social et professionnel, cliniques (ancienneté de la maladie, sévérité de la maladie, évaluation neuropsychologique), thérapeutiques, relatives à l’humeur, anxiété, coping, image corporelle, qualité de vie ; ii) auprès de l’aidant : données sociodémographiques, données relatives à l’environnement social et professionnel, lien avec le patient, donnée relatives à son propre état de santé, l’humeur, anxiété, coping, qualité de vie, fardeau. Déroulement : information du patient au cours d’une visite régulière, désignation d’un aidant, recueil de consentements, recueil des données.
Analyses statistiques : Pour répondre à l’objectif principal les scores de qualité de vie ‘patient’ seront confrontés aux différentes variables recueillies (test t de Student, coefficient de corrélation). Les résultats seront ajustés aux facteurs de confusion au moyen d’analyses multivariées. Pour répondre à l’objectif secondaire, les scores de qualité de vie et fardeau de l’aidant seront confrontés aux différentes variables recueillies selon le même procédé. La validation transculturelle de l’instrument PSP-QoL sera réalisée selon les standards usuels : méthode forward-backward, test acceptabilité, étude des propriétés métriques.
Résultats attendus et impact : Ce travail permettra une meilleure compréhension du handicap social associé à la PSP et pourra aboutir à l’application de nouvelles mesures thérapeutiques dans ce cadre.
Pertinence du projet au regard de l’état des connaissances : Il n’existe à l’heure actuelle aucune donnée en France sur la qualité de vie des personnes atteintes de PSP et le fardeau des aidants. En outre, les facteurs impactant particulièrement ces deux aspects sont mal connus. Le handicap moteur réduit naturellement la qualité de vie des patients et augmente le fardeau de l’aidant. En revanche l’impact des troubles cognitivo- comportementaux et notamment la réduction des interactions sociales sur la qualité de vie du patient et la charge de l’aidant a été assez peu étudiée.
Humanities and Social Sciences 2
2014Pascal ANTOINEVilleneuve d'AscqFoundation For Rare DiseasesHolt-Oram syndrome (HOS) - Nail Patella syndrome (NPS) - Rendu Osler disease (ROD)Impact of three rare genetic diseases: comparative and exploratory psychosocial researchContexte : Les connaissances sur le vécu et l’expérience des maladies rares sont limitées, car ces affections sont nombreuses, différentes dans leur expression, évolutivité et mode de transmission. Il est probable que ces aspects impactent le vécu et la qualité de vie de manière différente. Pour ce projet, nos deux équipes peuvent s’appuyer sur leurs expertises respectives sur les interactions sociales et familiales dans le domaine de la santé physique et mentale, et la génétique et le suivi des anomalies du développement, notamment des membres, et de la maladie de Rendu-Osler, ainsi que sur leur expérience de travail en commun.
Objectifs : Nous proposons un projet original étudiant trois maladies héréditaires rares avec les objectifs suivants:
1. Analyser le vécu des patients et évaluer leur qualité de vie afin d’améliorer les connaissances sur ces affections et, en les comparant, dégager les éléments impactant le plus le vécu.
2. Evaluer pour chacune, les représentations qu’ont les patients de leur maladie, de son histoire naturelle et des modalités de surveillance (suivi du parcours de soin).
Méthode: Nous étudierons 3 maladies héréditaires rares (syndrome de Holt-Oram, HOS, syndrome Nail Patella, NPS, et maladie de Rendu Osler, RO) transmises sur le même mode autosomique dominant avec variabilité d’expression, mais différentes dans leurs modes de révélation, leurs symptomatologies et leurs évolutions en nous appuyant sur nos files actives de patients et, pour la maladie de RO, avec l’aide de l’association AMRO.
La littérature actuelle en SHS étant limitée pour ces trois affections, cette recherche est basée sur les connaissances actuelles concernant les maladies chroniques en général, les caractéristiques des maladies rares et des maladies génétiques en particulier pour étudier :
1) L’expérience et le vécu des patients (retentissement fonctionnel, social et professionnel, détresse émotionnelle et difficultés d’ajustement)
2) La situation psychosociale, conditions d’accès au diagnostic, à l’information, aux soins et aides institutionnelles.
3) Les représentations associées à la maladie et leur influence sur le parcours de soin et la surveillance médicale puisque les 3 affections ont un risque de complications potentiellement graves, justifiant une surveillance adaptée dès le diagnostic. En effet, cette surveillance semble diversement mise en place et suivie dans le temps.
4) L’aide apportée par les associations de patients car seule le RO en possède une (AMRO- France).
Pour cette étude observationnelle et comparative transversale d’une durée de 24 mois, nous proposons une méthodologie mixte associant :
Une approche quantitative, qui permettra des comparaisons entre les groupes de patients touchés par les différents syndromes étudiés (analyses statistiques inférentielles) afin de 1) décrire les caractéristiques de chaque groupe, avant de les comparer entre eux, 2) mettre en relation les phénomènes étudiés (anxiété, dépression, adhésion thérapeutique) avec les représentations de la maladie, 3) identifier les caractéristiques cliniques qui prédisent le mieux la qualité de vie.
Une approche qualitative par Analyse Phénoménologique. Ce type d’approche, issue des évolutions récentes en psychologie qualitative, met l’accent sur la compréhension de l’expérience vécue par la personne. Elle implique une démarche « idiographique », chaque cas étant étudié en détail avant de tendre vers des conclusions plus générales présentées sous forme narrative. Cette analyse est particulièrement utile quand le domaine d’étude est dynamique, subjectif, récent ou relativement méconnu et lorsque des thèmes comme la détresse psychologique, la qualité de vie, l’identité ou la recherche de sens mobilisent les personnes concernées.
Critères d’inclusion et de non inclusion: seront inclus les patients atteints par HOS, NPS ou RO, âgés de plus de 18 ans et en mesure de signer un consentement libre et éclairé. Ne pourra pas être inclus tout patient présentant une comorbidité hors spectre des pathologies étudiées.
Résultats attendus et impact : Ce projet, original dans sa conception, a l’ambition non seulement de faire progresser les connaissances sur les conséquences individuelles et sociales, dans trois maladies héréditaires rares transmises sur le même mode autosomique dominant, mais aussi de dégager, grâce à la comparaison entre celles-ci, les éléments qui impactent le plus le vécu des patients et de leurs familles. Nos résultats permettront de proposer des recommandations pour l’amélioration de la prise en charge et l'accompagnement des personnes atteintes et de leurs proches, de sensibiliser les équipes soignantes et les pouvoirs publics aux particularités de ces pathologies.
Il permettra aussi de développer des outils (actuellement inexistants) permettant de mesurer les dimensions de l’altération de la qualité de vie subjective dans le cadre des maladies rares et de déboucher sur un projet de recherche interventionnelle portant sur l’accompagnement psychosocial, si nécessaire.
Pertinence du projet au regard de l’état des connaissances : ce projet s’attaque à un sujet quasiment vierge, les connaissances sur les impacts respectifs du HOS, du NPS et du RO sur le vécu des patients et de leurs familles étant inexistantes ou très limitées. Il constitue donc une expérience pilote et les données recueillies des éléments de référence. Ce protocole pourra ultérieurement être étendu à d’autres syndromes rares.
Humanities and Social Sciences 2
2014Drina CANDILIS HUISMANParisFoundation For Rare DiseasesRare diseases with movement disordersChildbirth and parenthood in women with motor disability related to rare diseasesContexte
La parentalité fait partie intégrante du parcours social et familial des personnes atteintes de maladies rares. Environ 10% des femmes en âge de procréer vivent avec un handicap entravant leur vie quotidienne Elles ont le même désir légitime de devenir mère que les autres femmes, mais se heurtent parfois aux réactions négatives de leur entourage ou des professionnels
Les femmes affectées par des maladies rares entrainant un trouble moteur constituent un groupe mal connu, ce qui contribue à leur stigmatisation. Ces maladies sont très diverses, et il n’est pas facile d’en établir la liste exhaustive. Elles partagent certaines caractéristiques : évolutivité au cours de la vie avec parfois un début dans l’enfance, fréquence du polyhandicap (atteinte des 4 membres, complications respiratoires...), fréquence des causes génétiques posant le problème de la transmission à la descendance, méconnaissance des enjeux de la maladie par la majorité des professionnels de santé, même spécialisés. On ne dispose pas de données spécifiques sur la parentalité chez les femmes atteintes de maladies rares entrainant des troubles moteurs aussi bien sur le plan de la littérature nationale qu’internationale.
Il est difficile d’établir une liste apriori des maladies rares entrainant un déficit moteur. Citons à titre d’exemple : maladies entrainant des mouvements anormaux, myopathies, malformations congénitales arrivées à l’âge adulte (spinabifida, spina lipome, autres malformations médullaires), autre causes rares de troubles moteurs chez des femmes jeunes (sclérose en plaque avec séquelles majeures, infirmité motrice cérébrales par séquelle de prématurité ou d’anoxie périnatale, tumeurs rares...)
Objectif :
Appréhender les enjeux spécifiques de la grossesse et la parentalité chez les femmes atteintes de maladies rares avec handicap moteur (groupe d’étude) en comparaison avec les femmes présentant un handicap moteur acquis fréquent (paraplégie post traumatique) et avec la population générale.
Méthodes : Nous utiliserons trois approches complémentaires :
1) Epidémiologie : Interrogation des bases de données de l’assurance maladie pour :
- estimer la fréquence de trois types de déficit moteur (paraplégie, tétraplégie, hémiplégie) chez les femmes en âge de procréer
- déterminer la part des maladies rares à l’origine de ces handicaps par analyse des codages par un groupe d’experts issu des centres de maladies rares
- évaluer la consommation de soins de santé en gynécologie obstétrique pour chaque groupe de handicap, stratifié par étiologie, en comparaison avec la population générale.
2) Sociologie: Enquête via internet (réseaux sociaux, association de patients, base de données des centres de maladies rares), portant sur les attentes des femmes en matière de soins de santé en parentalité et leur perception sur la capacité du système de santé à répondre à leurs attentes.
3) Psychologie périnatale: Etude rétrospective du parcours d’accession à la parentalité et étude observationnelle des modalités des interactions et de l’attachement portant sur un sous groupe de femmes ayant accouché depuis moins de 4 ans et identifiées à partir des bases de données des 2 sites de naissances, du service d’accompagnement à la parentalité des personnes en situation de handicap, du site de médecine physique et réadaptation, et des centres de référence participant à l’étude.
Résultats attendus
Estimation du nombre de femmes en âge de procréer présentant une paraplégie, une tétraplégie, ou une hémiplégie secondaire à une maladie rare. Détermination de leur consommation de soins de santé en matière de contraception, dépistage gynécologique, et maternité en comparaison avec la population générale et avec les femmes vivant avec un déficit moteur non lié à une maladie rare.
Détermination de la concordance entre les attentes des femmes et leur perception de l’offre de soin existante.
Détermination de la spécificité des modes d’interaction des dyades mères enfant et des modalités de construction de l’attachement de l’enfant chez les femmes vivant avec un déficit moteur lié à une maladie rare, en comparaison avec la population générale et avec les femmes vivant avec un déficit moteur non lié à une maladie rare
Impact potentiel
- Mieux connaitre les attentes des femmes, l’état actuel de l’offre de soins, et l’impact du handicap sur la relation mère enfant et l’attachement
- Proposer des stratégies en matière d’offre de soin en périnatalité, et d’accompagnement social ou psychologique
- Pour favoriser l’autonomie dans le choix de devenir mère pour les femmes vivant avec un handicap moteur résultant d’une maladie rare.
Humanities and Social Sciences 2
2014Damien LEGERParisFoundation For Rare DiseasesRare hypersomniaProfessional career path in patients with rare hypersomniasNarcolepsy is a rare hypersomnia, or severe wakefulness disorder, characterized essentially by sudden, invincible bouts of sleep that occur several times during the day. It is a rare and under-diagnosed condition, affecting between 0.025% and 0.05% of the population in France, or around 30,000 narcoleptics. This chronic, incapacitating and highly disabling condition persists throughout life, affecting all aspects of the patient's personal, social and family life.
At school, narcolepsy represents a loss of opportunity due to the difficulties caused by excessive daytime sleepiness in children.
At work, daytime sleepiness and the invincible sleep attacks characteristic of the disease are also a threat to the future, with difficulties in entering or staying in the workplace, leading to frequent job changes or even unemployment.
This underlines the importance of early diagnosis, proper treatment and appropriate career guidance. Unfortunately, very little is known about the occupational consequences of narcolepsy, and hypersomnias in general, and very few studies have been carried out on the subject.
Using both a clinical and an anthropological approach, including observations and interviews with patients, their families, friends and employers, this project aims to contribute to a better understanding of narcolepsy as experienced by patients: obstacles, restrictions, proscriptions in daily tasks and employment, but also strategies and recourse in personal and professional activities.
Thus, the main objective of our study is to better understand and describe the career path of patients with rare hypersomnia in two possible career periods: training and job-seeking, and working, with the aim of better professional integration.
Secondary objectives include : describe the type of disability and work restrictions associated with drowsiness, which are often attributed to causes other than the disease; analyze how these patients access and maintain employment; better understand the vulnerability and disruption of social ties in these patients; characterize the activity-sleep rhythm of these patients; provide patients, their families, the Association française des patients narcoleptiques et hypersomniaques (ANC) and occupational physicians with information guides and tools on the difficulties encountered in the workplace, with a view to improving patient orientation, support and information, and guiding them in their career paths.
Humanities and Social Sciences 2
2014Laurence FAIVRE-OLIVIERDijonFoundation For Rare DiseasesDevelopmental anomaliesPreferences and representations of progress linked to the introduction of high-throughput sequencing technologies with regard to practice in medical genetics: from the example of syndromes with developmental abnormalities.Contexte : Le diagnostic étiologique des maladies rares avec anomalies du développement reste encore trop souvent inconnu, ce qui est source d’errance médicale, de quête diagnostique prolongée et d’incompréhension de la part des familles. De plus, cela représente une potentielle perte de chance pour l’accès à un conseil génétique adapté, à un suivi optimal et à d’éventuelles ressources thérapeutiques. La dynamique des progrès observée ces deux dernières années en termes d’innovations technologiques permet d’entrevoir une véritable révolution dans le diagnostic, la recherche et la thérapeutique pour les patients. Après les découvertes diagnostiques possibles grâce à la généralisation des puces à ADN, le séquençage à haut débit (SHD) est en voie de transformer considérablement le domaine des pathologies du développement, de la recherche fondamentale au soin. Néanmoins, avant le transfert en pratique quotidienne, en particulier pour l’expertise diagnostique par le SHD d'exome, il est nécessaire de pouvoir anticiper l’information à communiquer aux patients et aux parents pour consentir à la réalisation du SHD d’exome. Ces questions dépassent l’usage des techniques, il s’agit d’un véritable enjeu sociétal, imposant d’associer des équipes des sciences humaines et sociales à la réflexion, et en particulier psychologues, sociologues, éthiciens, économistes de la santé, et des associations de patients. L’objectif en termes de santé publique est de permettre aux patients atteints de maladies rares de bénéficier de technologies innovantes dans des conditions d’information et d’accompagnement optimales.
Ce projet est à l’initiative de deux centres de références Maladies Rares Anomalies du Développement et Syndromes Malformatifs (interrégions Est et Centre-Est), qui se sont entourés de l’Espace de Réflexion Éthique Bourgogne/Franche-Comté, de l’Équipe d’Économie de la Santé (EES-LEDi UMR 6307 CNRS - université de Bourgogne), de l’équipe de recherche « Éthique et Progrès médical » spécialisée en méthodologie qualitative au sein de l’Inserm CIT 808 du CHRU de Besançon, du Centre Georges Chevrier (UMR CNRS 7366, axe « Soins, vie et vulnérabilité : éthique, rationalités et pratiques des sciences biomédicales»), et d’un collectif d’associations. Ce travail s’appuie sur l’expérience préalable des équipes sur le plan méthodologique et thématique (expérience préalable de l’équipe Lyonnaise qui a mené une étude qualitative du vécu des parents et des médecins après l’introduction de la CGH-array en pratique diagnostique, expérience de l’équipe d’économie de la santé dans les études de révélation des préférences, expérience de l’équipe du CIC-IT éthique dans les études qualitatives).
Objectifs : L’objectif de ce projet est
1/ d’évaluer les préférences des familles de patients atteints d’anomalies du développement vis-à-vis de la diffusion des résultats d’interprétation incertaine et fortuits du SHD, en amont des analyses d’exome réalisées en diagnostic, et
2/ de décrire, d’analyser et de comprendre, en aval des analyses d’exome réalisées en diagnostic, les vécus, attentes et réactions des familles et des généticiens vis-à-vis de leur trajectoire diagnostique en général et quant au moment de l’annonce des résultats du SHD en particulier.
Il s’agit de mieux appréhender les enjeux de l’usage diagnostic du SHD, notamment quant aux modalités d’information, de consentement et d’annonce des résultats. Ainsi, en étudiant ces situations à l’occasion du passage du SHD en diagnostic dans les deux centres de référence de Dijon et Lyon, le projet se place dans une perspective anticipatrice de la généralisation de ces pratiques cliniques en matière de prescription, d’annonce diagnostique et d’accompagnement des patients/familles.
Méthodologie :
La méthodologie comprend 2 approches complémentaires :
1/ Étude quantitative permettant de révéler les préférences des familles de patients atteints d’anomalies du développement vis-à-vis de la diffusion des résultats d’interprétation incertaine et fortuits du SHD, en amont des analyses d’exome réalisées en diagnostic. L’étude s’adressera aux parents de patients atteints d’AD venant consulter aux centres de référence de Dijon et de Lyon sur une période de 9 mois, et qui pourraient bénéficier du SHD dès lors qu’il serait proposé à titre diagnostic. Les questionnaires reposent sur la méthode des choix discrets (méthode innovante et reconnue en économie pour révéler les préférences individuelles) et seront élaborés par l’équipe pluridisciplinaire.
2/ Étude qualitative permettant de comprendre les vécus et représentations liées à l’utilisation de cette nouvelle technique de SHD à visée diagnostique à partir d’entretiens menés auprès des familles bénéficiant de cette technologie et des médecins généticiens les accompagnants dans cette démarche. Il s’agira d’analyser, en aval des examens pratiqués, quelles étaient leurs attentes et quelles sont leurs réactions. Les entretiens seront réalisés avec les parents ayant bénéficié d’une analyse d’exome pour leur enfant (10 situations pour lesquelles un diagnostic est posé suite à l’examen ; 10 situations pour lesquelles une anomalie est détectée mais de pathogénicité non certaine ; 10 situations pour lesquelles aucun élément nouveau n’est mis en évidence), selon les principes de la théorie ancrée édictés par Glaser et Strauss et avec une analyse thématique et conceptuelle continue des entretiens audio-enregistrées. Cette étude, en aval des examens d’exome proposés en diagnostic, permettra d’évaluer l’impact des modalités d'information et d’annonce des résultats.
Les questionnaires et guides d’entretien seront réalisés par l’équipe pluridisciplinaire, comprenant des représentants d’associations de malades.
Le choix s’est porté sur l’association d’une méthodologie quantitative et qualitative, pour allier les avantages et pallier aux limites de chaque méthodologie, permettant ainsi d’étudier les phases en amont et en aval d’une technologie de SHD. En effet, l’étude quantitative permettra d’interroger un nombre important de patients sur la phase en amont de l’indication d’un test de SHD et ainsi de garantir une certaine représentativité de la population, tout en autorisant la mise en évidence de comportements hétérogènes au sein de cette population. L’étude qualitative ne permet d’interroger qu’un nombre limité de patients mais permet de décrire, analyser et comprendre en profondeur des phénomènes complexes en aval des résultats d’un test de SHD. L’exploration de la phase d’amont et d’aval apparait indispensable compte tenu de l’ambition de pouvoir proposer des livrables utilisables sur le plan national. Les équipes proposant ces deux approches complémentaires font partie du même comité de pilotage, ce qui sera une richesse pour la conduite de l’étude.
Résultats attendus et impact : Les résultats de ces deux études auront des répercussions opérationnelles en termes d’anticipation de l’annonce, de formation des médecins, de mise en place de supports pédagogiques adaptés pour les familles, de pistes de réflexion pour la rédaction des consentements à un échelon national, de discussion sur la mise en place d’une meilleure organisation des soins. Ce projet contribuera à favoriser la transition de la recherche aux soins pour que les patients atteints de maladies rares et leurs familles puissent bénéficier plus rapidement de technologies innovantes dans des conditions d’information et d’accompagnement optimales.
Ce projet pourra servir à tous les autres domaines de la génétique. Sur le plan de la santé publique, il permettra d’anticiper l’accès au SHD du plus grand nombre pour une optimisation amélioration de la prise en charge le plus précocement possible.
Livrables :
Les résultats de ce projet permettront d’élaborer et de faire valider :
1/ des modèles de contenu des notes d’information et des formulaires de consentement spécifiques à ces situations,
2/ un guide d’aide à l’annonce des résultats,
3/ des supports à visée pédagogique pour les familles.
Le projet débouchera aussi sur des publications internationales pour faire connaître l’avancée des connaissances dans le domaine des préférences et représentations vis-à-vis de la nouvelle technologie du SHD et des attentes en termes d’annonce et d’accompagnement.
Pertinence du projet au regard de l’état des connaissances : En l’absence de réglementation nationale d’utilisation de cette technologie, il est nécessaire que soient initiées des réflexions sur les informations à communiquer et les modalités d’accompagnement des familles, afin d’anticiper l’arrivée du SHD à titre diagnostique en pratique quotidienne. Les méthodologies proposées (méthode des choix discrets et entretiens individuels qualitatifs) sont à la fois adaptées à la problématique et reconnues comme innovantes dans la littérature.
Humanities and Social Sciences 2
2014Philippe CHARRONParisFoundation For Rare DiseasesHereditary cardiac diseasesPredictive genetic testing in hereditary cardiac diseases:
Evaluation of psycho-social impact and multidisciplinary management
Background: Hereditary heart disease is a rare genetic disorder, but a major cause of sudden death and heart failure in young people under 40. Cardiac expression is often delayed into adulthood, and so-called "predictive" genetic testing is proposed for asymptomatic relatives, to identify those who are not at risk of developing the disease, and to identify those who should benefit from targeted medical management and early initiation of therapy. However, the psycho-social impact of predictive genetic testing is poorly understood, and the precise modalities of support during the genetic consultation vary widely from team to team.
The 1st objective is to assess the psychological and socio-professional impact of revealing genetic status on people at risk of developing hereditary heart disease who have undergone predictive genetic testing.
The 2nd objective is to take stock of the organization of predictive test consultations in France (pre-genetic test and post-test consultation, presence or absence of cardiologist, presence or absence of psychologist, reflection period or not before blood sampling) and to assess the influence of this medical organization on the psychological and socio-professional impact of consultants. Methods: The project concerns adult relatives who are undergoing, or have undergone, predictive genetic testing for hereditary heart disease. It comprises three separate studies.
1/ Prospective multicenter study. The study will be carried out in a few selected centers, using self-questionnaires (quantitative and qualitative scales) filled in by consultants (100 to 150 subjects) at three different times (before consultation, before results are returned, after results are returned). The impact of the genetic result will be analyzed by weighting according to various parameters. A more in-depth semi-structured interview consultation with a clinical psychologist will also be offered to a sub-group of consultants.
2/ National retrospective study. The study will be carried out using self-questionnaires (quantitative and qualitative scales) sent by all volunteer French centers to the homes of consultants seen in the past in genetic consultation for predictive testing (400 subjects). The self-questionnaires are given out only once, and at a distance from the genetic results.
3/ National survey of genetic services in France. A survey of the organization of genetic consultations will be carried out by sending questionnaires to the various practitioners involved in genetic consultations in France. The information will then be used to weight the interpretation of the questionnaires completed by the consultants.
Impact: The results will provide innovative and decisive information on the practice of predictive genetic testing in France and its psychosocial impact. The lessons learned will be used to revise the methods used to support and carry out predictive genetic consultations in hereditary heart disease, with the definition of new optimal methods to be proposed to French centers in order to harmonize practices and the care pathway in France.
Our project is based on strong interactions between teams with complementary expertise (reference center for these pathologies, university clinical psychology team, biostatistics team), who have already collaborated in the past and recently reported preliminary work on the impact of predictive testing in hereditary heart disease (oral communication at congress).
Humanities and Social Sciences 2
2014Sonia ABDELHAKTunisFoundation For Rare DiseasesConsanguinity and hereditary rare diseaseConsanguinity and hereditary rare diseases : challenges and perspectives in post genomics -TWAS
2015Pauline ARNAUDParisFoundation For Rare DiseasesMarfan Syndrome and related disorders, Familial Thoracic Aneurysm and Dissection (FTAAD)Identification of new genes involved in Marfan Syndrome and Familial Thoracic Aneurysm and Dissection (FTAAD) -High throughput sequencing 2015 - 1
2015Isabelle AUDOParisFoundation For Rare DiseasesRetinitis pigmentosa (RP)Gene defect identification in X-linked retinitis pigmentosa cases excluded for currently known gene defects -High throughput sequencing 2015 - 1
2015Nadia BAHI-BUISSONParisFoundation For Rare DiseasesPeriventricular Nodular HeterotopiaInvestigating novel modular basis for Periventricular Nodular Heterotopia -High throughput sequencing 2015 - 1
2015Stephanie BAULACParisFoundation For Rare DiseasesEpilepsyIdentification of new genes for autosomal dominant focal epilepsies -High throughput sequencing 2015 - 1
2015Patrick CALLIERDijonFoundation For Rare DiseasesPai syndromeIdentification of the gene for Pai syndrome through Whole Genome Sequencing -High throughput sequencing 2015 - 1
2015Vincent CANTAGRELParisFoundation For Rare DiseasesCerebellar atrophy associated with intellectual disabilityGenetic basis of childhood-onset cerebellar atrophy associated with intellectual disability -High throughput sequencing 2015 - 1
2015Nadia CERF-BENSUSSANParisFoundation For Rare DiseasesEarly onset inflammatory intestinal diseasesDetermination of mendelian causes of intestinal inflammation -High throughput sequencing 2015 - 1
2015Nicolas CHASSAINGToulouseFoundation For Rare DiseasesAnophthalmia - microphthalmiaAnalysis of regulatory elements sequences in microphthalmia/anophthalmia -High throughput sequencing 2015 - 1
2015Jamel CHELLYStrasbourgFoundation For Rare DiseasesFocal cortical dysplasia - EpilepsyGenetics of Focal Cortical Dysplasias -High throughput sequencing 2015 - 1
2015Alexandre FABREMarseilleFoundation For Rare DiseasesSyndromic diarrhea/tricho-hepato-enteric syndrom Identification of new genes associated with syndromic diarrhea/ tricho-hepato-enteric syndrom -High throughput sequencing 2015 - 1
2015Sylvain LATOURParisFoundation For Rare DiseasesRare primary immunodeficienciesMolecular identification of novel forms of inherited lymphoproliferation syndromes associated with a susceptibility to EBV infection -High throughput sequencing 2015 - 1
2015Valerie MALANParisFoundation For Rare DiseasesIntellectual disability and congenital malformations Unmasking of a recessive mutation: what role in the incomplete penetrance of CNVs -High throughput sequencing 2015 - 1
2015Sandrine MARLINParisFoundation For Rare DiseasesCochlear nerve AplasiaIdentification of the molecular basis of cochlear nerve aplasia -High throughput sequencing 2015 - 1
2015Sophie NAUDIONBordeauxFoundation For Rare DiseasesA new entity (glomerular disease-lymphoedema-hypotrophy-developmental delay-immune deficiency) Identification of the molecular bases of a new phenotype of multiple malformations in a multiplex family -High throughput sequencing 2015 - 1
2015Veronique PAQUIS-FLUCKINGERNiceFoundation For Rare DiseasesMitochondrial diseases Identification of new genes responsible for mitochondrial disorders by exome sequencing -High throughput sequencing 2015 - 1
2015Nathalie ROUX-BUISSONGrenobleFoundation For Rare DiseasesExertional Heat Stroke syndrome (EHS)Identification of new genes in Exertional Heat Stroke syndrome (EHS) with positive in vitro contracture test and no mutation in RYR1 gene -High throughput sequencing 2015 - 1
2015Stephane VIVILLEStrasbourgFoundation For Rare DiseasesInfertilityGenetics of male infertility: genes implicated in non-obstructive azoospermia -High throughput sequencing 2015 - 1
2015Christina ZEITZParisFoundation For Rare DiseasesRetinitis pigmentosa (RP)Identification of novel gene defects underlying retinitis pigmentosa in France by whole exome sequencing -High throughput sequencing 2015 - 1
2015Marie-Christine ALESSIMarseilleFoundation For Rare DiseasesPlatelet dysfunctionIdentification of new genes involved in platelet dysfunction -High throughput sequencing 2015 - 2
2015Christine BELLANNÉ-CHANTELOT ParisFoundation For Rare DiseasesCongenital neutropeniaIdentification of new genes in congenital neutropenia -High throughput sequencing 2015 - 2
2015Alain CALENDERLyonFoundation For Rare DiseasesSarcoidosis (Besnier-Boeck-Schaumann disease)Identification of genes involved in familial forms of sarcoidosis -High throughput sequencing 2015 - 2
2015Pascale DELONLAYParisFoundation For Rare DiseasesRhabdomyolysis and Reye syndromeIdentification of the gene(s) responsible for recessive rhabdomyolysis and Reye syndrome in 3 patients from 2 families presenting the same phenotype -High throughput sequencing 2015 - 2
2015Muriel GIRARDParisFoundation For Rare DiseasesBiliary atresiaIdentification of a common signaling pathway involved in biliary atresia -High throughput sequencing 2015 - 2
2015Celine HUBERParisFoundation For Rare DiseasesAsphyxiating Thoracic Dysplasia or Jeune syndromeIdentification of the molecular basis of the Asphyxiating Thoracic Dysplasia -High throughput sequencing 2015 - 2
2015Vincent LAUGELStrasbourgFoundation For Rare Diseases Cockayne syndromeInvestigating novel molecular basis for Cockayne syndrome -High throughput sequencing 2015 - 2
2015Caroline MICHOTParisFoundation For Rare DiseasesMicrocephalic osteodysplastic primordial dwarfismsDissection of molecular bases of microcephalic osteodysplastic primordial dwarfisms: identification of new genes in pre-screened patients -High throughput sequencing 2015 - 2
2015Veronique PAQUIS-FLUCKLINGERNiceFoundation For Rare DiseasesMitochondrial diseases Progressive external ophthalmoplegia with multiple mitochondrial DNA deletions: identification of new genes -High throughput sequencing 2015 - 2
2015Laurent PASQUIERRennesFoundation For Rare DiseasesRhombencephalosynapsisIdentification of a gene involved in rhombencephalosynapsis -High throughput sequencing 2015 - 2
2015Megana PRASADStrasbourgFoundation For Rare DiseasesBardet-Biedl and Bardet-Biedl-like syndromesIdentification of novel genes underlying Bardet-Biedl and Bardet-Biedl-like syndromes -High throughput sequencing 2015 - 2
2015Pierre RAYGrenobleFoundation For Rare DiseasesNon-obstructive azoospermiaIdentification of genetic causes of human non-obstructive azoospermia -High throughput sequencing 2015 - 2
BordeauxFoundation For Rare DiseasesRight ventricular hypoplasiaIdentification of a gene involved in familial right ventricular hypoplasia -High throughput sequencing 2015 - 2
2015Agnes RÖTIGParisFoundation For Rare DiseasesMitochondrial disease with neurological involvement Identification of nuclear genes responsible of abnormal respiratory chain assembly -High throughput sequencing 2015 - 2
2015Pascale BOMONTMontpellierFoundation For Rare DiseasesGiant Axonal Neuropathy (GAN)Reversing motor deficits in GIant Axonal Neuropathy Giant Axon Neuropathy (GAN) is a neurodegenerative disease that begins in childhood and leads to a fatal outcome in young adulthood. No treatment is available to prevent or ameliorate the severe symptoms, which induce progressive loss of walking, sensation and severe deficits in the brain. While research is advancing into the mechanisms responsible for this disease, no laboratory has been able to create a mouse model reproducing the pathology. We have now developed the 1st animal model for NAG, reproducing the severe neurological disorders found in patients, and propose to implement it for the benefit of patients, in the search for new treatments. To this end, we propose to undertake the 1st pharmacological mass screening for NAG. This study will enable us to identify molecules active against NAG and thus envisage future preclinical development for patients.High-throughput screening 2014
2015Vincent GACHELyonFoundation For Rare DiseasesCentronuclear Myopathies (CNM)Rescue myonuclear domains establishment in centronuclear myopathies with chemical compoundsCentronucleated myopathies (CNM) are muscle diseases characterized by the persistent abnormal positioning of nuclei in muscle fibers.
During muscle formation, specialized cells fuse to form multi-nucleated cells which, after maturation, become muscle fibers. The nuclei of these fibers are first positioned in the center, then migrate to the periphery to shape the nuclear domains of each fiber. Poor positioning of the nuclei in the early phases of fiber formation is correlated with a defect in the formation of these nuclear domains, which are responsible for the functional integrity of the fibers.
Our preliminary data have identified an early defect in the localization of nuclei in fibers in a mouse model of CNM. The aim of this study is to identify new molecules that will restore the correct localization of nuclei in CNM muscle fibers.
Ultimately, this study will enable us to identify new therapeutic targets in the context of developing and diseased muscle.
High-throughput screening 2014
2015Yvon TROTTIERStrasbourgFoundation For Rare DiseasesHuntington's diseaseHigh Throughput screening for the identification of amyloid aggregation modulators in Huntington's diseaseHuntington's disease (HD) is a neurodegenerative disorder with no known cure. HD, like Alzheimer's, Parkinson's and other diseases, is characterized by the accumulation in the brain of protein aggregates known as "amyloid". Although inhibiting amyloid aggregation has been shown to be effective in treating familial amyloid polyneuropathy, there is as yet no effective inhibitor for HD. Our research team has developed an innovative technology, called SynAggreg, designed to identify amyloid aggregation inhibitors from screens of large chemical compound libraries.
In this project, we intend to adapt and use SynAggreg to identify specific inhibitors of the amyloid responsible for HD. These inhibitors will then be tested in animal models of HD to establish their potential to prevent disease symptoms, a necessary step prior to clinical applications.
High-throughput screening 2014
2015Johann BOHM IllkirchFoundation For Rare DiseasesTubular aggregate myopathy and Stormorken syndromeFirst mammalian model for tubular aggregate myopathy and
Stormorken syndrome
Muscle diseases affect children and adults in all populations, but their molecular basis is poorly understood. Without detailed knowledge of the pathomechanisms of these rare diseases, it is very difficult to develop therapeutic approaches. Our team recently identified the first gene (STIM1) associated with tubular aggregate myopathy, and demonstrated that this muscle disease is due to a muscle calcium imbalance. Calcium induces contraction and is a key factor in muscle function. As many muscle diseases are the consequence of a muscle calcium imbalance, tubular aggregate myopathy represents an excellent model to study the correlation between calcium homeostasis and muscle weakness. We propose to generate a mouse model carrying the most recurrent and severe STIM1 mutation, associated with a multi-system phenotype described as Stormorken syndrome, in order to study in detail the development of the disease and test initial therapeutic strategies in preclinical settings.Mouse models 2014
2015Pascale BOMONTMontpellierFoundation For Rare DiseasesGiant axonal neuropathyDevelopment of an In vivo model for Giant Axonal Neuropathy Giant Axon Neuropathy (GAN) is a rare, fatal neurodegenerative disease of young adults for which there is currently no cure. Extremely severe, NAG leads to a loss of mobility and sensitivity in young children, and then targets the central nervous system, causing intellectual, vision and language disorders. In order to study the neurodegenerative mechanisms in NAG and develop new methodologies for clinicians/geneticists and patients, our laboratory has identified the NAG gene, generated diagnostic tools, and created cellular and animal models of the pathology. In particular, we have generated a mouse model of NAG, but this does not reproduce the severity of the human disease and thus considerably limits the pre-clinical trials needed to develop therapy in patients. This project aims to generate a new type of mouse model reproducing NAG pathology, which will enable us not only to dissect the mechanisms of death in NAG but also to test and validate new therapeutic approaches for this fatal and incurable pathology.Mouse models 2014
2015Jamel CHELLYIllkirchFoundation For Rare DiseasesMalformations of Cortical Development - Periventricular Nodular Heterotopia (PVNH) Understanding NEDD4L-related MCD (Malformations of Cortical Development) through investigations of a Knock-In mouse model Our recent work using the WES approach in MDC patients has led to the identification of mutations in a set of genes encoding proteins involved in the regulation of protein ubiquitination. Among these genes is NEDD4L, which codes for a protein containing an E3 ubiquitin ligase domain. Further targeted analysis of NEDD4L identified two additional mutations associated with periventricular nodular heterotopias (PVHN) clinically characterized by ID and epilepsy.
Our main objective is to better characterize the neurodevelopmental abnormalities associated with NEDD4L mutations. We therefore propose to develop a KI mouse model carrying the mutation, Nedd4l - p.R897Q, identified in a patient whose MRI revealed PVNH, and to carry out studies:
- behavior and susceptibility to epilepsy
- neurodevelopmental processes, with a focus on progenitor proliferation, neuronal polarization and migration
- molecular networks disrupted by Nedd4l dysfunction, by undertaking expression studies and proteomic analysis.
The results of these studies should contribute to a better understanding of the pathophysiological mechanisms involved in MCDs, and could also help identify potential targets that could be exploited to modulate epilepsy severity.
Mouse models 2014
2015Helene DOLLFUSStrasbourgFoundation For Rare DiseasesCiliopathy-like phenotype associating kidney alteration and retinal degenerationMouse modeling of a missense mutation in the essential gene PIK3R4 (VPS15) responsible for a ciliopathy-like disease A sequencing analysis of the coding parts of the genome of various members (diseased or not) of a family presenting a clinical picture suggestive of ciliopathy (renal impairment, retinal degeneration) revealed a missense mutation in the PIK3R4 gene (VPS15). This gene codes for a protein essential for the synthesis of a lipid, PI3P, a key component of membranes. The name of the VPS15 gene comes from the baker's yeast in which it was discovered and named Vps15 for "vacuolar protein sorting 15". Studies in zebrafish and baker's yeast show that the pathological mutation VPS15R998Q is responsible for cellular defects linked to cilium function (fish) and vesicular trafficking (yeast). A mouse mimicking the human mutation in the VPS15 gene (VPS15R998Q knock-in mouse) is essential on a pathophysiological level in order to link clinical manifestations to ciliary dysfunctions. From a fundamental point of view, this knock-in mouse will enable many laboratories around the world to gain a better understanding of the PI3P synthesis pathway and its role in the cell. The scientific interest is complemented by a potential therapeutic interest, as numerous studies are underway to modulate these lipid synthesis pathways in order to act in various fields of medicine (neurology, myopathy, cancer, infectious diseases).Mouse models 2014
2015Julie DUMONCEAUXParisFoundation For Rare DiseasesFacioScapuloHumeral Dystrophy (FSHD)FacioScapuloHumeral Dystrophy (FSHD): targeting two alternative Fat1 exons with one mouse FacioScapuloHumeral Dystrophy (FSHD) is one of the most common muscular diseases for which there is no palliative or curative treatment. It is mainly characterized by atrophy of the shoulder, face and arm muscles. Although the genetic cause is known (loss of a piece of chromosome 4 in the vast majority of patients), the molecular and cellular mechanisms that lead to the disease's symptoms are not yet clearly understood. We have recently demonstrated the involvement of a new gene (called FAT1) in the onset/progression of this pathology. Until now, however, no-one had realized the importance of this gene in muscle physiology. Studying this gene is tricky, because at DNA level, it is very large and gives rise to several different proteins. The aim of our project is to create a mouse model in which some of these alternative forms of FAT1 protein will be eliminated. Such mice will make it possible (i) to identify the form of FAT1 required for proper muscle function and (ii) to develop a therapeutic approach for FSHD.Mouse models 2014
2015Christian HAMELMontpellierFoundation For Rare Diseases Vitelliform macular dystrophies (VMD)Impg1 gene Knock-Out, a mouse model for human vitelliform macular dystrophy and retinitis pigmentosa The human retina is made up of different cell types essential for vision, including photoreceptors and retinal pigment epithelial (RPE) cells. Photoreceptors and RPE are separated by a very thin layer, the interphotoreceptor matrix (IPM). This IPM enables the retina to adhere and function properly within the eye. We have discovered that mutations in two major components of this ILM, the SPACR and SPACRCAN proteins, are responsible for vitelliform macular dystrophy and retinitis pigmentosa. These diseases are hereditary degenerative disorders of the retina, leading to blindness in the most severe forms. The concept that PIM is an important player in lipofuscin accumulation is novel. Lipofuscin is a cellular pigment composed of debris molecules which is characteristic of vitelliform macular dystrophy and, more generally, of numerous retinal pathologies such as AMD, the leading cause of blindness in France. The development of mice that do not express these two proteins will enable us to gain a better understanding of the pathophysiological mechanisms of the disease and the development of innovative therapies.Mouse models 2014
2015Alain HOVNANIANParisFoundation For Rare DiseasesRecessive Dystrophic Epidermolysis BullosaGeneration of a humanized mouse model for Recessive Dystrophic Epidermolysis Bullosa harbouring a recurrent COL7A1 mutation Epidermolysis bullosa recessiva (EBDR) is a rare and severe genetic disease of children and adults, responsible for skin and mucous membrane detachments from birth. The disease is due to mutations in the COL7A1 gene encoding collagen VII, which is essential for the adhesion of the superficial layer of the skin to the middle layer. There is currently no specific treatment for EBD, and skin cancer is the most frequent cause of death in these young patients.

This research project aims to develop a new mouse model carrying the mutated human version of the COL7A1 gene to the exclusion of the mouse version of the gene. The mutation introduced into the human gene is a mutation very frequently found in patients. These mice are expected to develop signs of the disease and will be studied in great detail. In the future, they will be used to test the feasibility and in vivo efficacy of new gene therapy approaches based on DNA double-strand cutting and nuclease repair.
Mouse models 2014
2015Sebastien LACROIX-DESMAZESParisFoundation For Rare DiseasesHemophilia AGeneration of a novel mouse model of hemophilia A constituted of mice transgenic for a human T cell receptor specific for therapeutic factor VIIITreating hemophilia A patients with therapeutic factor VIII induces an immune response that renders the treatment ineffective. This makes it very difficult to treat bleeding patients. Our aim is to develop a new murine model of hemophilia A using transgenic mice in which the majority of T cells are specific for factor VIII. Unlike existing animal models, in which only a tiny proportion of T cells recognize factor VIII, this new model will enable us to study in great detail the cellular and molecular interactions that characterize the development of the immune response against therapeutic factor VIII. These mice will be an unrivalled tool for dissecting this immune response, for testing the safety of new genetically engineered therapeutic factor VIII, and for monitoring the innate immune response in hemophilia A patients throughout their lives. The development of this model should ultimately improve the management of hemophilia A patients. Mouse models 2014
2015Carine LE GOFFParisFoundation For Rare DiseasesMyhre syndrome (MS)SMAD4 and Myhre syndromeMyhre syndrome (MS) is a developmental disease characterized by short stature, short extremities and joint stiffness. It is also associated with complications such as arterial hypertension, bronchopulmonary insufficiency and obesity leading to early death. We have identified mutations in the SMAD4 gene in 30 MS patients. In cells from MS patients, deregulation of the TGFβ pathway was observed. SMAD4 is also known to be a tumor suppressor. However, to date, MS patients have not developed cancer.
MS is a unique model that can allow us to study both bone and cartilage development.
Our aim is therefore to study the function of SMAD4 in these processes. To do this, we want to develop a mouse model that mimics the MS. Secondly, we will study the functional consequences associated with mutations in the SMAD4 gene.
This project will enable us to discover new target molecules with potential spin-offs for the treatment of SMAD4-related cancers.
Mouse models 2014
2015Delphine MEYNARDToulouseFoundation For Rare DiseasesIron Refractory Iron Deficiency Anemia (IRIDA)Is matriptase-2 involved in iron homeostasis regulation and anemia exclusively through the hepatocytes? IRIDA syndrome is an inherited disorder characterized by severe anemia that can only be partially corrected by iron supplementation. The disease is due to a defect in the expression of the matriptase-2 protein. It is currently accepted that the absence of matriptase-2 in the liver leads to increased expression of hepcidin, thus blocking the entry of iron into the body. However, the severity of the anemia observed is disproportionate to the level of hepcidin. Furthermore, erythropoietin injections in IRIDA patients have no effect on their anemia.
This suggests that matriptase-2 may have a role in erythropoiesis, independent of hepcidin through an extrahepatic function. To investigate this possibility, we propose to produce mice expressing no matriptase-2 in the liver only, and to assess their degree of anemia.
Full characterization of matriptase-2 function will improve our understanding of IRIDA syndrome and anemia in general. This may help in the development of new therapies to correct anemia in IRIDA patients.
Mouse models 2014
2015Veronique PAQUIS-FLUCKINGERNiceFoundation For Rare DiseasesMotor neuron disease and ataxiaCHCHD10S59L mouse model: how mitochondrial dysfunction promotes motor neuron disease? Amyotrophic lateral sclerosis (ALS), also known as Charcot's disease, is a neurodegenerative disease that affects the motor neurons, leading to death within 3 to 5 years of diagnosis. There is no cure for this terrible disease, which is mostly accidental but can run in families in 5 to 10% of cases. We have recently identified a new gene, CHCHD10, responsible for ALS but also for other pathologies that include motor neuron damage. This gene encodes a mitochondrial protein whose function we have begun to study. To understand how mitochondrial dysfunction leads to motor neuron death, we need a mouse model which is as close as possible to the human disease, and which will also enable us to test new therapeutic strategies.Mouse models 2014
2015Frederique RENEStrasbourgFoundation For Rare DiseasesAmyotrophic Lateral Sclerosis (ALS)Generation of an ALS-FTD mouse model based on a conditional CHMP2B intron 5 mutant Knock-InAmyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. Between 10% and 20% of ALS patients also develop behavioral disorders due to fronto-temporal dementia (FTD). To date, there is no curative treatment for this pathology, and the mechanisms leading to neuronal death have not been fully elucidated. Mutations in the CHMP2B gene have been identified in patients with ALS, ALS-FTD and FTD. Recent data have shown that the intron5 mutation is capable of inducing neuronal death in vitro. Moreover, transgenic mice overexpressing this mutant develop certain aspects of the pathology.
In this project, we propose to generate a mouse that will conditionally express this mutant in one or 2 alleles of the Chmp2B gene. These mice, which will closely mimic the genetic changes described in humans, will enable us to study the cellular and molecular mechanisms that lead to the pathology, and to propose new therapeutic avenues.
Mouse models 2014
2015Frederic RIEUX-LAUCATParisFoundation For Rare DiseasesPrimary immunodeficiency with autoimmunityRole of LRBA in the control of the immune response: implication in primary immunodeficiencies Several international teams, including our own, have identified a deficiency of the LRBA gene in pediatric patients with susceptibility to infections and autoimmune manifestations. To date, little is known about the role of this molecule, and the mechanisms of the pathology remain to be discovered in order to provide these patients with specific therapeutics. Our aim is to generate a mouse deficient in the LRBA gene, in order to study the functions of this gene in the immune response and to provide a model for studying human pathology.Mouse models 2014
2015Sophie ARBORIOVillers les NancyFoundation For Rare DiseasesWest syndrome, severe epilepsy West Syndrome: construction of knowledge and experiences of singularity familiesThe' present' research' is' based' on' a' multidisciplinary' team' comprising' two' doctors,' two' health' anthropologists' and' four' patient' associations. Through' an' anthropological' problematic,' it' intends' to' better' understand' the' modalities' of' knowledge' construction' relative' to' two' aspects' of' the' life' course' of' families':' the' identification' of' the' disease' and' the' therapeutic' management' of' patients' suffering' from' West' syndrome.' This' severe' form' of' infant' epilepsy' is' a'rare'disease'and'disability'whose'characteristics'call'into'question'the'knowledge'of'the'disease'in'its'more'conventional'forms,'particularly'in'the'context'of'the'doctor-patient'relationship' (deficit'of'diagnostic'knowledge,'discreet'and'unusual'symptomatology,'characterization' of'the'disability'situation..),'but'also'in'the'forms'of'management'that'result'(side'effects'of'medication,'therapeutic'regimen,'lack'of'adapted'structures).' Here,' West'syndrome'is'approached'both'as'a'specific'form'of'epilepsy'and'as'a'disease'emblematic' of'cross-cutting'issues'common'to'various'severe'epilepsies'(notably'tuberous'Bourneville's'sclerosis).'''
The' aim' of' the' research' is' to' characterize' and' discern' the' place' of' families' experiential' knowledge' in'identifying'the'disease'and'treatment.'The'knowledge'analyzed'is'derived'from'the'point'of'view'of'families'-'and'patients'where'possible'-'and'will'ultimately'enable'this'lived'experience'to'be'better'taken'into'account'within'the'framework'of'therapeutic'patient'education'(TPE).'
The' ethnographic' methodology' is' based' on' interviews' with' families' (60),' observations' (hospitalizations,' day' hospital' and' complementary' examinations' (EEG' and' MRI)' and' TPE' sessions)'and'analysis'of'Facebook'corpus'(pages'"'STB'"'and'"'Children'of'West'").
Humanities and social sciences 3
2015Michel CASTRALilleFoundation For Rare DiseasesCystic Fibrosis and Idiopathic Pulmonary Fibrosis (I.P.F.)Disability and discrimination in the working place and in daily life in the pre-transplant period.
A comparative study between two rare pulmonary diseases: cystic fibrosis and Idiopathic Pulmonary Fibrosis (I.P.F.).
Using a multi-disciplinary approach (sociology, philosophy, law, psychology and
and comparative approach between two diseases (cystic fibrosis and
Pulmonary Fibrosis
F.P.I.), the aim of this study is to investigate how patients and their families experience the disease
families in the pre-transplant period, i.e. at a time when disability is most keenly felt (physically (weight loss, fatigue), psychologically (anxiety, uncertainty or stigma)), and has the greatest impact on their social participation. The comparison between the two diseases is particularly interesting. Diagnosed at birth, cystic fibrosis leads patients and their families to "build" their lives around the disease and the prospect of a long-term transplant. For patients with F.P.I., diagnosed at around 50/60 years of age, the symptoms of the disease come on suddenly for the patient and his or her family, and the prospect of a transplant may present itself rapidly (6 months) after the disease has been diagnosed. We hypothesize that the experience of the disease at this time varies according to a series of factors: the temporality of the disease (short (2 to 5 years without transplantation for F.P.I.) or longer for cystic fibrosis), the patient's social identity (being a young adult or an aging individual), family identity (being single, in a couple, a parent or grandparent) and professional identity (being at the beginning or end of one's working life), an "anticipated socialization" to the transplant or the existence of a major
patient association.
With this in mind, we will carry out 60 semi-structured interviews and 30 observations with patients and their close circle.
half for each disease.
The results of this research are intended to raise medical teams' awareness of the experience of the disease for patients and their families in the pre-transplant period, and to help them consider appropriate support measures to improve the quality of life of patients and their families.
to improve disease management during this period.
Humanities and social sciences 3
2015Dominique FARGEParisFoundation For Rare DiseasesSystemic sclerosis, LupusEstablishment of a collaborative e-platform to identify and characterize the handicaps of patients with rare autoimmune diseases within the cell therapy or biotherapyTo improve care and support for patients with disabilities linked to a rare autoimmune disease (AID), we need to know how the disease impacts their daily lives, by listening to them talk about their life course. Research in the human and social sciences (SHS) on this theme is based on what these patients experience, as they invent solutions to preserve their quality of life, their health and their very lives. E-FORM-Innov proposes to bring together 3 research teams (patients, SHS researchers, medical and care teams) who will work together to produce knowledge in this field. Patient volunteers are considered as co-researchers, in view of the questions they ask and the solutions they propose, after a short research training course. By creating a virtual community of 36 patients suffering from a rare IAD (systemic scleroderma or lupus), the aim is to invite them to transform their knowledge into organized knowledge about what they experience on a daily basis, the strategies they invent and the solutions they find to overcome their disability. These patients are invited to tell their life story in front of a third party, to describe and analyze what they do, how they do it and how they transform themselves to pursue their personal development despite their illness. They have a surplus of daily tasks "in the service of keeping themselves alive", which far exceeds their therapeutic obligations. They may have to choose between their care priorities and their quality of life. To generate knowledge, we propose to mobilize "collective intelligence", bringing together individual intelligences to create a dynamic of cooperation, thanks to a "collaborative virtual platform" on a dedicated website. Digital tools (virtual lounges, chatrooms, etc.) will be made available to patient-users to facilitate their exchanges with each other, with other researchers and with the community manager (CM). The CM will lead the exchanges, with the aim of answering the question: how can we identify and characterize the disabilities of patients suffering from a rare IAM requiring cell therapy or biotherapy?Humanities and social sciences 3
2015Anne MARCELLINIMontpellierFoundation For Rare DiseasesDown syndrome, 22q11 deletion, Williams-Beuren syndrome Becoming an adult with developmental anomalies: obstacles and facilitatorsThe term "developmental anomalies" covers a wide variety of "rare diseases" that can lead to delays in intellectual development, more or less associated with behavioral disorders. In our society, these two types of difficulties are the ones that produce the most serious handicap situations for the people concerned. The aim of this research is to understand how people affected by these developmental anomalies can achieve a satisfying adult life. The study will focus on a population of adolescents and young adults (aged 16-25) affected by three rare diseases - trisomy 21, 22q11 deletion and Williams and Beuren syndrome - diversifying the profiles according to criteria of level of behavioral disorders, family and social situation, schooling and social participation. In-depth interviews will be conducted separately with the young people, their parents and possibly their siblings, in order to understand the recurring obstacles and facilitators encountered by the young people in their educational, professional, leisure and access to emotional and sexual life trajectories. The expected results will shed light on the practices and questions of professionals in the field and families concerning the educational and professional orientation of these young people, their support in social and affective life, the management of information concerning medical labeling and the analysis of its affective, identity, family and social consequences. The aim is to improve the quality of support for these people as they move towards independent adulthood.Humanities and social sciences 3
2015Gregoire MERCIERMontpellierFoundation For Rare DiseasesLymphedemaThe LYMPHO-RAC study: analyzing out-of-pocket payments of primary lymphedema patients in FrancePrimary lymphedema is a rare, chronic and debilitating disease that causes swelling and pain in a part of the body.
Primary lymphedema (prevalence 1 to 5 per 10,000) is caused by a failure of the lymphatic system during childhood or adolescence, affecting both children and adults, and leading to functional disability. It is responsible for serious infectious complications that profoundly alter patients' future quality of life, with a sometimes very significant economic impact on the family.
Its treatment relies on medical devices that are poorly reimbursed, resulting in a cost to the patient known as Reste à Charge (RAC). This RAC threatens equity of access to care.
The main aim of the LmyphoRAC study is to estimate the RAC for adults and families of children suffering from primary lymphedema.
It is a prospective study of usual care in several French cities. Associations, doctors and other healthcare professionals working in the field of lymphedema in several locations in France have committed themselves to motivating the participation of patients and their families. The LymphoRAC data collection system is innovative. It relies heavily on the commitment of patients to connect via the Internet to anonymous electronic questionnaires and to fill them in. The data collected will not be able to identify patients, and will be accessible only to the study's principal investigator.
From a collective point of view, this study will provide a better understanding of the cost of lymphedema management, the amount of out-of-pocket expenses for patients, and the degree of equity in the distribution of out-of-pocket expenses in the population and in access to appropriate care for patients.
Humanities and social sciences 3
2015Remy POTIERParisFoundation For Rare DiseasesUsher, Wolfram and Stickler syndromes Psychosocial determinants of deafblindness handicap on autonomy within the life path of people affected with Usher, Wolfram and Stickler syndromes Multiple disabilities are now a major social concern, as evidenced by the preparation of a specific decree. The aim of this interdisciplinary research project is to provide civil society (from patients to public authorities) with the tools it needs to consider the impact on subjects' autonomy of the deaf-blindness bi-disability associated with the genetic syndromes of Usher, Wolfram and Stickler, using the category of "identity construction" to capture the variety of situations affected by this bi-disability. We'll be working on the interaction between SHS psychology, sociology and anthropology, to contribute to and broaden medical care and the life course.
The results of this research will be offered to patients and associations for a participatory exchange, before being published and promoted.
The aim is to harness the synergy of SHS to make a direct contribution to quality of life.
Humanities and social sciences 3
2015Sophie QUINTONLilleFoundation For Rare DiseasesSystemic sclerosisScleroderma and occupational difficulties: identify to better helpBACKGROUND: systemic scleroderma is a rare disease of the immune system responsible for multiple disabilities that differ from one patient to the next. Few studies have looked at the impact of this disease on patients' working lives, so we don't know exactly what difficulties are encountered, nor what solutions or resources are implemented to alleviate them.
OBJECTIVES: The primary objective of the study is to estimate the frequency of occupational difficulties in patients with Scl. The secondary objectives are to identify these difficulties, their knowledge of and access to common entitlements and the disabilities involved.
METHODS: A questionnaire designed in partnership with scleroderma specialists, a humanities and social sciences researcher and a patient association will be offered to patients with systemic scleroderma as part of their disease follow-up at the Lille University Hospital over a 12-month period, with the aim of obtaining a minimum of 100 responses (from a cohort of around 500 patients).
RESULTS: The expected results are a better understanding of the difficulties of reconciling work and disability linked to the disease, of the difficulties of maintaining employment, of functional difficulties and of the extent of the lack of awareness of certain measures to help maintain employment. An interventional phase resulting from this study will aim to set up 1) an early intervention scheme targeting the risk factors of professional disengagement for patients suffering from Scl or another connective tissue disease having a disability in common with Scl, 2) draw up an information document for patients and their carers on the legal provisions and practical professional aids to encourage job retention, and 3) organize meetings and debates to raise awareness of these pathologies among companies. The aim is to promote job retention in line with patients' different disabilities.
Humanities and social sciences 3
2016Genevieve BAUJATParisFoundation For Rare DiseasesKlippel Feil syndromeMolecular basis dissection of isolated Klippel Feil syndrome: identification of new genes -GenOmics 2016 - 1
2016Stephane BÉZIEAUNantesFoundation For Rare DiseasesSyndromic and non-syndromic severe intellectual disability (IQ<50)Trio-based whole-genome sequencing of patients with syndromic and non-syndromic severe intellectual disability -GenOmics 2016 - 1
2016Celia CRÉTOLLEParisFoundation For Rare DiseasesCurrarino Syndrome (non mutated for MNX1 gene)
Syndromic caudal dysgenesis: Ano-rectal malformation associated with partial sacral agenesis and occult dysraphism and pre sacral tumor
Genotype-endophenotype correlation study in patients with a MNX1 gene non mutated Currarino syndrome -GenOmics 2016 - 1
2016Yanick CROWParisFoundation For Rare DiseasesAicardi-Goutieres syndrome
Type I interferonopathies
Familial chilblain lupus
Whole genome sequencing in Aicardi-Goutieres syndrome and related type I interferonopathies -GenOmics 2016 - 1
2016Albertina DE SARIOMontpellierFoundation For Rare DiseasesCystic FibrosisDNA methylation and pulmonary disease in cystic fibrosis patients - GenOmics 2016 - 1
2016Christel DEPIENNEStrasbourgFoundation For Rare DiseasesFamilial cortical myoclonic tremor and epilepsy (FCMTE) Identification of the unconventional genetic basis for familial cortical myoclonic tremor and epilepsy -GenOmics 2016 - 1
2016Pascale GUICHENEYParisFoundation For Rare Diseases
Long QT syndrome (LQTS)
Catecholergic polymorphic ventricular tachycardia (CPVT)
Elucidation of the molecular variants responsible for sudden cardiac death in two large families -GenOmics 2016 - 1
2016Alice HADCHOUELParisFoundation For Rare DiseasesPulmonary alveolar proteinosisIdentification of a new gene in a familial form of pulmonary alveolar proteinosis -GenOmics 2016 - 1
2016Eric LE GUERNParisFoundation For Rare DiseasesGenetic generalized epilepsyIDENTIFICATION OF NEW GENES FOR FAMILIAL FORMS OF GENERALIZED EPILEPSIES -GenOmics 2016 - 1
2016Guy LENAERSAngersFoundation For Rare DiseasesMitochondrial Inherited Optic Neuropathies
Dominant Optic Atrophy
Kjer disease
Genetic analysis of dominant optic atrophy - GenOmics 2016 - 1
2016Caroline MICHOTParisFoundation For Rare DiseasesCornelia de Lange syndromeDissection of molecular bases of Cornelia de Lange syndrome: identification of new genes in pre-screened patients -GenOmics 2016 - 1
2016Jean MULLERStrasbourgFoundation For Rare DiseasesBardet-Biedl SyndromeIdentification of novel genes underlying Bardet-Biedl Syndrome using Next Generation Sequencing -GenOmics 2016 - 1
2016Christian PINSETParisFoundation For Rare DiseasesDuchenne muscular dystrophy (DMD)Studying myogenesis and the onset of Duchenne muscular dystrophy (DMD) in human pluripotent stem cells to identify early disease markers and potential therapeutic targets -GenOmics 2016 - 1
2016Amelie PITONStrasbourgFoundation For Rare Diseasesintellectual disability
Evaluation of RNA-sequencing strategies to better diagnose intellectual disability - GenOmics 2016 - 1
2016Angela TINGAUD-SEQUEIRABordeauxFoundation For Rare DiseasesGoldenhar syndrome
Oculo-auriculo-vertebral spectrum
Exome sequencing to find new candidate genes involved in Goldenhar Syndrome and Oculo-Auriculo-Vertebral Spectrum -GenOmics 2016 - 1
2016Sandrine VUILLAUMIER-BARROTParisFoundation For Rare DiseasesCDG syndrome, glycosylation defect, coagulation defectIdentification of a gene underlying same coagulation factors abnormalities and CDG II profile in two unrelated families with anticipated dominant transmission. -GenOmics 2016 - 1
2016Marie-Christine ALESSIMarseilleFoundation For Rare DiseasesETV6-related thrombocytopeniaUNRAVELING MOLECULAR MECHANISMS OF ETV6-RELATED THROMBOCYTOPENIA -GenOmics 2016 - 2
2016Mathieu BARBIERParisFoundation For Rare DiseasesFrontotemporal-Lobar Dementia (FTLD)IN SEARCH OF GENETIC MODIFIERS TO PREDICT THE AGE AT ONSET IN FRONTOTEMPORAL-LOBAR DEMENTIA -GenOmics 2016 - 2
2016Louise BENARROCHParisFoundation For Rare DiseasesMarfan syndrome
Familial Thoracic Aortic Aneurysm and Dissection
2016Valerie CORMIER-DAIREParisFoundation For Rare DiseasesGenochondromatosisIDENTIFICATION OF THE MOLECULAR BASIS OF GENOCHONDROMATOSIS - GenOmics 2016 - 2
2016Alexandre FABREMarseilleFoundation For Rare DiseasesWaldmann's disease or Primary intestinal lymphangiectasiaGENETIC BASES OF PRIMARY INTESTINAL LYMPHANGIECTASIA -GenOmics 2016 - 2
2016Anne JOUTELParisFoundation For Rare DiseasesHereditary cerebral small vessel diseaseDISSECTING MOLECULAR PATHWAYS INVOLVED IN COL4A1-RELATED INTRACEREBRAL HEMORRHAGE -GenOmics 2016 - 2
2016Jocelyn LAPORTEStrasbourgFoundation For Rare DiseasesMuscular dystrophy
Congenital myopathy
2016Roland LIBLAUToulouseFoundation For Rare DiseasesNarcolepsy with cataplexyHUMAN IMMUNE SIGNATURES OF NARCOLEPSY WITH CATAPLEXY - GenOmics 2016 - 2
2016Valerie DESQUIRET-DUMASAngersFoundation For Rare DiseasesMitochondrial complex I deficiencyScreening of pharmacological molecules to restore oxidative metabolism in rare diseases associated with mitochondrial complex I mutations.Complex I deficiencies account for up to 30% of mitochondrial diseases. These devastating pathologies, linked to a defect in energy production, have no curative treatment. Our results show, in fibroblasts from patients with complex I structural defects, a blockade of substrate entry into the mitochondria.
of substrates into the mitochondria and glycolytic metabolism, leading to severely slowed cell growth. The aim of this project is to screen for molecules that can improve cell growth by overcoming the blockage of mitochondrial energy synthesis. This parameter will enable an initial simple screening; hits will then be validated by more detailed analyses of mitochondrial metabolism. The identification of molecules capable of overcoming the metabolic blockage induced by structural defects in complex I could lead to the wider treatment of other rare diseases linked to alterations in mitochondrial function.
High throughput screening 2016
2016Michel FONTESMarseilleFoundation For Rare DiseasesX-linked Charcot-Marie-Tooth disorder (CMTX)HTS screening to identify molecules correcting connexon activity in CMTX disorder.We have created transgenic mouse lines expressing the protein mutated in the disease and showing a locomotor deficit. This involves Calmodulin Kinase type II, and inhibitors of this enzyme correct the phenotype of the cells and halt the degradation of locomotor abilities. Finally, we were able to show that cells from CMTX patients displayed the same abnormalities. This has enabled us to develop a screen for the disease's primary deficit, connexon activity. We propose to use these tools to identify molecules capable of restoring normal connexon activity. Chemical libraries will be screened on the PICBS platform in Strasbourg. Molecules identified in this way will be validated using cells from CMTX patients. We thus hope to define drug candidates that could be used in clinical trials on patients.High throughput screening 2016
2016Sylvie FOURNEL-GIGLEUXNancyFoundation For Rare DiseasesMucopolysaccharidosesSearch for inhibitors of the galactosyltransferase β4GalT7 by High Throughput Screening: towards a specific substrate reduction therapy in mucopolysaccharidosesMucopolysaccharidoses (MPS) are rare genetic diseases caused by a deficiency in the enzymes that break down glycosaminoglycans (GAGs) or mucopolysaccharides. They accumulate in cells, leading to serious multi-organ damage, particularly in the brain, and shortening life expectancy. Objective-Develop less burdensome treatments to improve neurocognitive symptoms. We will search for a small molecule that specifically inhibits an enzyme that constructs GAGs in order to reduce their accumulation and deleterious effects. To this end, we will screen a large number of molecules at high
molecules. We have patented a fluorescence assay which will be miniaturized and robotized on a dedicated platform, in order to discover molecules blocking the activity of the target enzyme, which will then be validated on MPS patient cells.
As most of the molecules screened are already on the market, we hope to quickly come up with a new treatment for MPS.
High throughput screening 2016
2016Mathieu RODEROParisFoundation For Rare DiseasesSTING-associated vasculopathy with onset in infancy (SAVI)Identification of molecules able to control interferon beta transcription in patients with gain-of-function mutations in TMEM173.We have discovered that genetic modifications affecting the STING molecule create a rare genetic disease that is generally very severe, and can affect the skin, lungs and blood vessels. Patients with this disease have bodies that behave as if perpetually infected by a virus. They produce large quantities of antiviral molecules called "interferon". Unfortunately, these molecules are toxic if produced in excessive quantities. Two INSTITUT IMAGINE teams specializing in the study of interferon-related diseases have joined forces to develop a strategy for the identification, optimization and therapeutic use of molecules capable of blocking interferon production in these children.High throughput screening 2016
2016Pierre CATTANParisFoundation For Rare DiseasesDevelopmental anomalies and malformation syndromes, esophageal atresia, esophageal carcinoma, esophageal caustic injuryFull thickness circumferential esophageal replacement by a tissue engineered construct in a porcine model. - Preclinical research 2016
2016Aziz EL-AMRAOUIParisFoundation For Rare DiseasesUsher syndrome type I (USH1), retinopathiesModeling the Usher syndrome type I (USH1) retinopathy in pig: physiopathology and gene therapy -Preclinical research 2016
2016Olivier GOUREAUParisFoundation For Rare DiseasesSensory disorders (rare eye diseases and deafness), Rod-cone dystrophies (retinitis pigmentosa), Cone-rod dystrophiesPreclinical validation of a stem cell-derived Retinal Pigmented Epithelium (RPE) in non-human primates -Preclinical research 2016
2016Gerard LAMBEAUValbonneFoundation For Rare DiseasesRare kidney diseases Rare systemic and autoimmune disorders, idiopathic Membranous NephropathyMembranous nephropathy, a rare autoimmune kidney disease: establishing the first model in non-human primates -Preclinical research 2016
2016Yann AUDICRennesFoundation For Rare DiseasesEpidermolysis bullosaXENOPUS EPIDERMIS DEVELOPMENT IN THE SEARCH FOR MODIFIER GENES OF EPIDERMOLYSIS BULLOSAEpidermolysis bullosa is caused by mutations in genes encoding components of the dermal-epidermal junctions. There is considerable variability in disease severity between patients from the same sibling. This variability is thought to be due to the existence of modifier genes that make patients more or less ill. Inactivation of the RNA-binding protein Ptbp1, highly expressed in the skin, leads to the development of epidermal blisters in the xenopus embryo. We have identified itga6 and tp63 as 2 major players in epidermal differentiation whose splicing is controlled by Ptbp1. We will block expression of epithelial forms of itga6 and tp63 to study the phenotype of
the phenotype of treated embryos. We will generate animals with one copy of the gene modified and study whether Ptbp1 inactivation of the other copy alters the phenotype, making Ptbp1 a modifier gene.
Small animal models 2016
2016Charles-Henry COTTARTParisFoundation For Rare DiseasesCystic fibrosisA NEW RAT MODEL FOR CYSTIC FIBROSIS CARRYING THE F508DEL MUTATION IN THE CFTR GENECystic fibrosis is the most common of rare diseases. It is a fatal genetic disease that mainly affects the lungs, but also other organs. In cystic fibrosis, the CFTR protein is either not produced or abnormal. 80% of sufferers carry the F508del mutation. Promising corrective molecules have been synthesized to correct the effects of this F508del mutation. Mouse models are used in preclinical studies, but they poorly mimic lung pathology. A rat model that does not express the CFTR protein has shown the presence of lung damage that is not seen in mice, but it does not allow us to test molecules that correct the F508del mutation. The aim of this work is to develop a rat model with the F508del mutation, which should enable us to evaluate corrective molecules and in particular their protective effects on cystic fibrosis lung damage.Small animal models 2016
2016Benjamin DEHAYBordeauxFoundation For Rare DiseasesKufor-Rakeb Syndrome
Neuronal Ceroid Lipofuscinosis
PHYSIOPATHOLOGICAL CHARACTERIZATION OF A RAT MODEL OF KUFOR-RAKEB SYNDROMEMutations in the ATP13A2 gene are associated with both Kufor-Rakeb syndrome and neuronal ceroid-lipofuscinosis. The clinical manifestations are progressive motor and cognitive disorders
with visual impairment. The course of the disease is invariably fatal. To date, there is no treatment available to halt or slow down the degenerative process. Two murine animal models have recently
have recently been developed, showing modest motor dysfunction without any neuronal loss, which is a feature of human pathology. To overcome this blockage, we propose to develop a rat model of the disease. The rat is a model of choice for biomedical research. The possibility of studying two different diseases by analyzing a single gene, ATP13A2, makes this approach promising, and will contribute to understanding these hitherto little-studied pathologies.
Small animal models 2016
2016Bruno DELLA GASPERAParisFoundation For Rare DiseasesSpinal muscular atrophy with respiratory distress (SMARD1) also called autosomal recessive distal spinal muscular atrophy-1 (DSMA1)XENOPUS TROPICALIS MODEL OF SPINAL MUSCULAR ATROPHY WITH RESPIRATORY DISTRESS (SMARD1) Distal spinal muscular atrophy type 1 (SMARD1) is a genetic disorder caused by mutation of the IGHMBP2 gene. This pediatric disease is characterized by loss of motor neurons, leading to distal muscle weakness and respiratory distress. Life expectancy is around 1 year, and there is no treatment to date. The aim of this project is to create a new animal model of this disease, based on
the amphibian xenopus, which has the advantage of being completely external in development, and can be studied and modified easily using current techniques. This transgenic model will enable us to better understand this disease and easily test drugs for therapeutic purposes.
Small animal models 2016
2016Laurence LEGEAI-MALLETParisFoundation For Rare DiseasesFGFR3-related osteochondrodysplasias (chondrodysplasias and craniosynostoses)ZEBRAFISH MODEL OF FGFR3-RELATED SKELETAL DISORDERSMutations in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene are responsible for the most common forms of dwarfism
both the most common forms of dwarfism, achondroplasia, and craniostenosis, Muenke's syndrome.
Muenke syndrome. The mechanisms controlling craniofacial ossification and axial skeleton formation
are poorly understood. The establishment of zebrafish lines expressing respectively
a mutation responsible for dwarfism or craniostenosis, respectively, will enable us to better understand the skeletal anomalies induced by these mutations. Indeed, the zebrafish is a model of choice for the study of craniofacial skeletal development, due to its many homologies with mammals. These models will also enable us to identify new therapeutic approaches, the zebrafish being an excellent model for screening molecules.
Small animal models 2016
2016Brigitte LELONGTParisFoundation For Rare DiseasesNephronophtisisIMPACT OF ANKS3 HUMAN MUTATION IN RAT MODELNephronophthisis is a chronic tubulointerstitial disease, i.e. an abnormality initially localized in the renal tubules and the interstitial tissue surrounding these tubules. There are three clinical forms, depending on the age of onset of the disease. It is a rare disease, affecting 1/100,000-1/50,000 people, and is the leading cause of end-stage renal failure in childhood. The disease is both clinically and genetically heterogeneous. Although 20 genes responsible for the disease have been identified, the genetic cause has yet to be determined in 50% of patients. S. Saunier's group has recently identified a new gene, ANKS3, responsible for the disease in humans. The aim of this project is to provide an animal model that will enable us to detail the expression, function and interactions of ANKS3 with other partners, thereby providing new information on this disease.Small animal models 2016
STUDY OF THE PHYSIOPATHOLOGY OF RNU4ATAC-ASSOCIATED DISEASESSeveral steps are necessary before our genes can be expressed in our cells. One of these is splicing, which removes unnecessary material from messenger RNAs, leaving only that required for protein production. We have shown that a defect in a component of the splicing machinery, U4atac, is responsible for the TALS syndrome, which results in numerous malformations (including severe brain malformations), intellectual disability and death before the age of 2-3 years. Our aim is to identify the consequences of the U4atac defect at the cellular level and on the scale of an animal model, the zebrafish, in order to discover new genes necessary for the proper development of the organism, in particular the brain, and to better understand its various stages. Our study will enable better clinical management of TALS patients and, more generally, of patients with cerebral malformations and their families.Small animal models 2016
2016Gilles MILLATLyonFoundation For Rare DiseasesEndocardial Fibroelastosis
Dilated Cardiomyopathy
PRKAG2 MUTATIONS AS A MOLECULAR EXPLANATION ON PATIENTS WITH DILATED CARDIOMYOPATHY AND ENDOCARDIAL FIBROELASTOSIS? Endomyocardial fibroelastosis is a common cause of unexplained heart failure in children.
It results from diffuse thickening of the endocardium, leading to dilated cardiomyopathy in most cases.
cases. The incidence has been estimated at 1 in 5000 births. Endomyocardial fibroelastosis is diagnosed between 3 and 6 months of age in most cases. Approximately 10% of cases are familial, but the molecular aspects associated with this type of cardiomyopathy remain poorly understood. Sequencing of a panel of over 40 genes involved in cardiomyopathies identified a homozygous PRKAG2 truncating mutation in an infant who died at 2 months of cardiogenic failure, and whose autopsy showed endomyocardial fibroelastosis. The aim of creating this zebrafish PRKAG2 ko model is therefore to confirm that PRKAG2 truncating mutations, in an autosomal recessive mode, can lead to cases of endomyocardial fibroelastosis.
Small animal models 2016
2016Christophe SIRACLimogesFoundation For Rare DiseasesAL amyloidosisEESTABLISHMENT OF A RAT MODEL FOR AL AMYLOIDOSISWhen plasma cells (antibody-secreting cells) proliferate, abnormal antibodies can aggregate and deposit in various organs, leading to their destruction. The study of these pathologies requires the use of reliable experimental models, which not only provide a better understanding of the disease, but also enable the testing of innovative therapeutic strategies. For many years now, our laboratory has been developing transgenic mouse models to reproduce these pathologies, but these animals appear to be resistant to AL amyloidosis, one of the most serious diseases that can result from these antibody deposits. However, the rat model appears to be a credible alternative for reproducing this pathology in a physiological model close to humans. Our aim is to develop a transgenic rat model expressing an abnormal human antibody, in order to reproduce AL amyloidosis and test innovative therapeutic approaches.Small animal models 2016
2016Helene AMIEVABordeauxFoundation For Rare DiseasesFronto-Temporal Lobar DegenerationsPersonalized and multidisciplinary care on behavioral disorders of Fronto-Temporal Lobar Degenerations / Prise en charge pluridisciplinaire et personnalisée des troubles du comportement dans la Dégénérescence Lobaire Fronto-TemporaleFronto-Temporal Lobar Degeneration (FTLD) is a serious, neurodegenerative disease that falls into 3 categories: Fronto-Temporal Dementia, Primary Progressive Aphasia and Semantic Dementia. This degeneration, which is related to Alzheimer's disease, generally occurs early, between the ages of 55 and 65, and is characterized by the appearance of significant behavioral and personality disorders, which vary from patient to patient, and are particularly difficult to manage. Because DLFT is not recognized by mainstream healthcare services, the healthcare system does not meet the expectations and needs of these patients and their families. Thus, people with DLFT and their carers need the healthcare system to identify and recognize them, and to provide them with appropriate support and follow-up through specific, personalized actions carried out by a multidisciplinary professional team trained in these pathologies.
The aim of the present project is to evaluate the usefulness of personalized multidisciplinary home-based intervention in the management of behavioral disorders in DLFT sufferers, followed up by
in Aquitaine, and the support of their family carers, in comparison with usual care. It will aim to provide them with health, social and/or psychological responses that are as close as possible to their needs, and will promote patients' social participation, notably through the use of compensatory strategies put in place by their family carers, and by strengthening recourse to and coordination with the social support network. Finally, one of the major spin-offs of this study will be to help raise awareness of DLFT, which is still under-appreciated, and to develop a psychosocial care strategy based on the skills of professionals from not only the health field, but also the medico-social and voluntary sectors.
Humanities and social sciences 4
2016Delphine DELLACHERIELilleFoundation For Rare DiseasesDevelopmental anomalies and malformation syndromesDance as a new tool for remediation in rare cerebellar developmental pathologies / TEMps et DANse comme outil de remédiation du fonctionnement dans les anomalies de développement du CErveletThe main aim of this research project is to promote the social integration and academic success of children with a rare developmental pathology of the cerebellum, using dance as a new remediation tool. The cerebellum is a "little brain" located at the back of the brain and comprising 50% of our neurons. Children with cerebellar disorders present cognitive deficits that are the source of complex handicap situations, and for which there are no specific means of compensation. The processing of time, crucial to everyday life, seems to be affected in these patients, particularly the natural ability to move in rhythm with sounds or music. Recent research suggests that this universal ability, also known as "sensory-motor synchronization", has a strong influence on cognition, learning and social interaction. The aim is therefore to test a new dance program designed to stimulate sensory-motor synchronization and, in so doing, improve patient functioning. In order to verify the benefits of dance, we will conduct a study on twelve patients aged 8 to 12 with congenital cerebellar anomalies. We will first analyze the deficits present before the start of the dance program. Then, the children will follow dance sessions twice a week for one month. Finally, we will evaluate the children's progress by comparing pre versus post intervention results in the temporal, motor, cognitive and social spheres. In the long term, this project should provide solutions to the social and therapeutic isolation of children with developmental abnormalities of the cerebellum, as well as contributing to the management of other neurodevelopmental pathologies linked to the cerebellum and which can lead to temporal cognition disorders, as is the case, for example, in dyslexia.Humanities and social sciences 4
2016Caroline DESOMBRELilleFoundation For Rare DiseasesRare non-malignant hematological diseases How to restore equality of opportunity for students with hemophilia? / Élèves touchés par l'hémoPHILie et autres maladies hémorragiques familiales : cOmMENt rétablir l'Egalité des chances à l'écoleThe aim of this research program is to combat the discrimination suffered by children with hemophilia by raising awareness among their parents, teachers and peers, in order to re-establish equal opportunities.
The aim is to highlight the fact that the negative image of the haemorrhagic disease that these children carry excludes them from some of the experiences they should be having. This exclusion can lead to a spiral of failure, with less success at school and less ambitious life choices. Indeed, a body of work in social psychology indicates that success at school is largely a reflection of
how parents and teachers believe their children can succeed. In turn, the child will adopt the adults' position and feel able or unable to succeed at school.
In order to verify that this insidious phenomenon can have an impact on the academic success of a certain number of children with hemophilia, we will begin by analyzing the discourse conveyed about the disease. We will interview young people aged between 6 and 19, and compare their representations with those of their parents and teachers. We will then show how these representations can constitute a threat and a stress that handicap these children when they are faced with school tests. These results should enable us, in the third phase, to propose concrete actions to restore equal opportunities for pupils affected by hemophilia: we will develop a pedagogical game on a digital environment by involving the various participants in this research. We will also be offering training courses for teachers. Finally, AFH will distribute a brochure and offer training courses for families to counteract these effects.
Humanities and social sciences 4
2017Dominique BONNEAU AngersFoundation For Rare DiseasesRare Intellectual disabilitiesOmics for Improving the Diagnosis of Rare Intellectual DisabilitiesBackground
Genetic factors play a major role in intellectual disability (ID), but the underlying cause is far from always being determined.
This project is a continuation of the HUGODIMS inter-regional project, in which we performed exomic sequencing of 69 carefully selected trios including a single child with ID and both parents. The genetic cause of ID was determined or strongly suspected in 48 cases (69.5%), and 7 new ID genes were identified.
We hypothesize that an approach combining genomics with transcriptomic, metabolomic and morphological analyses performed on neuronal cells derived from induced pluripotent stem cells (iPSCs), could improve the diagnosis and understanding of ID. The aim of this project is to demonstrate that this "multi-omics" approach is relevant and effective.
Materials and methods
Ten people with ID whose exomic sequencing did not lead to a diagnosis will be included.
The study design is as follows:
1. Whole genome sequencing for the 10 negative trios (Nantes)
2. Bioinformatics analysis
3. For 3 negative cases after genome sequencing, as well as for 3 positive controls carrying
a mutation in the CAMK2a gene (identified by HUGODIMS) and 3 healthy negative controls:
a) Derivation of neural progenitors from iPSCs (Nantes platform)
b) Targeted and non-targeted metabolomic analyses of 9 neuronal cell lines
c) Transcriptomic analysis of the 9 cell lines (Rennes)
d) Morphological analysis of neural cells obtained from affected subjects and positive
positive controls carrying CAMK2a mutations (Tours)
e) Integration and validation of multi-omics and morphological data.
Expected results and impact
We expect this multi-omics approach to improve diagnosis and understanding of ID.
2017Jean-Baptiste GOURRAUDNantesFoundation For Rare Diseaseslong QT syndrome, idiopathic ventricular fibrillationCIQTP prolongation: role and mechanism in sudden cardiac deathMalgré les progrès importants du dépistage clinique et génétique, la majorité des morts subites survenant chez des sujets jeunes (<45ans) demeurent inexpliquées. L’identification des mécanismes conduisant à ces arrêts cardiaques est pourtant primordiale pour prévenir et traiter les arythmies à risque de mort subite. Nous avons récemment mis en évidence un nouveau syndrome héréditaire caractérisé par un électrocardiogramme normal au repos mais présentant lors d’un stress mental un allongement de l’intervalle QT responsable de morts subites. L’objectif de notre étude est de mieux comprendre le mécanisme et l’importance de ce syndrome dans la mort subite du sujet jeune.
A cette fin nous commencerons par réaliser, en plus du dépistage conventionnel, un test de stress mental lors du dépistage de familles atteintes de mort subite inexpliquée ou de syndrome du QT long (arythmie héréditaire présentant un allongement de l’intervalle QT au repos avec risque de mort subite). Cette partie de l’étude, réalisée dans les CHU de Brest, Nantes, Rennes et Tours permettra d’identifier de nouveaux patients atteints par ce syndrome et de préciser sa présentation clinique en comparant les anomalies observées au repos et lors des tests de dépistage pour ce syndrome et le syndrome du QT long.
L’étude se poursuivra par une analyse génétique de 4 familles afin d’identifier les gènes responsables de ce syndrome. Parmi ces quatre mêmes familles, des cellules cardiaques seront générées à partir de 3 patients appartenant à chacune d’entre elles ce qui offrira la possibilité de rechercher les modifications d’expression des gènes et de courants ioniques à l’origine de ce syndrome.
2017Laurent PLANTIERTowersFoundation For Rare DiseasesIdiopathic Pulmonary FibrosisAcoustic Waves and Helium/oxygen for Aerosol Treatment of Idiopathic Pulmonary Fibrosis (IPF)Idiopathic pulmonary fibrosis (IPF) is a rare disease with a very poor prognosis. Innovative inhalation (aerosol) treatments for IPF are currently being developed in our laboratory. To date, the use of aerosols for the treatment of IPF has been limited by the fact that they are mainly deposited in the best-ventilated, i.e. least diseased, regions of the lung. The aim of this project is to develop a method to overcome this limitation.
In the laboratory, we will use a device that models healthy and diseased regions of the respiratory tract to determine whether the application of acoustic waves of different frequencies, the use of a helium/oxygen mixture (Heliox®), the application of continuous positive airway pressure (CPAP), or the performance of maneuvers simulating deep inspirations (IP), increase the deposition of a medicated aerosol (salbutamol) in the affected regions. Effective interventions will then be combined to identify an optimal aerosolization protocol.
Next, we will conduct a clinical study in IPF patients to determine whether the optimal protocol delivers enhanced deposition of a model aerosol, compared with the conventional technique (without acoustic waves, helium/oxygen, CPAP, or IP). To precisely quantify deposition in diseased and healthy regions of the patient's lung, we will combine CT images, which enable fine analysis of lung structures, with single-photon emission computed tomography (SPECT) images, which enable three-dimensional visualization of aerosol deposition traced by a radioelement, 99mTechnetium. The safety of the aerosolization protocol will be verified by repeated measurements of respiratory function and symptom questionnaires.
This project will be developed by a multidisciplinary team including physicians and engineers specialized in IPF, aerosol generation and medical image analysis.
2017Brahim BELBELLAAIllkirchFoundation For Rare DiseasesFreidreich Ataxia associated cardiomyopathyMultisystem approach analysis of friedreich ataxia cardiomyopathy in frataxin-deficient mice models and hIPS-derived cardiomyocytes for the elucidation of pathophysiological mechanisms and identification biomarkers. -GenOmics 2017 - 1
2017Virginie CARMIGNACDijonFoundation For Rare DiseasesCLOVES: Congenital Lipomatous Overgrowth, Vascular Malformations and Epidermal Nevi syndrome
MCAP: Megalencephaly-Capillary Malformation-Polymicrogyria syndrome
KTS: Klippel Trenaunay Syndrome
Unraveling the genetic basis of mutation-negative mosaic overgrowth syndromes through deep whole exome sequencing -GenOmics 2017 - 1
2017Martine COHEN-SALMONParisFoundation For Rare DiseasesMegalencephalic leukoencephalopathy with subcortical cystsDeciphering the gliovascular functions of MLC1 underlying megalencephalic leukoencephalopathy -GenOmics 2017 - 1
2017Genevieve de SAINT BASILEParisFoundation For Rare DiseasesX-Linked thrombocytopenia, Woodhouse Sakatti, IgA nephropathy, Severe Immune disorder, VasculopathyGenetic basis of various phenotypes segregating in a large inbred family -GenOmics 2017 - 1
2017Claire FRANCASTELParisFoundation For Rare DiseasesICF syndrome: Immunodeficiency Centromeric instability Facial anomaliesGenOmics of the ICF syndrome: when studying a rare disease also sheds new light on the "old" field of DNA methylation -GenOmics 2017 - 1
2017Cecile JEANPIERREParisFoundation For Rare DiseasesCongenital anomalies of the kidney and urinary tract (CAKUT)
Renal hypodysplasia (RHD)
Identification of novel genes and mutational mechanisms for renal hypodysplasia -GenOmics 2017 - 1
2017Sandrine MARLINParisFoundation For Rare DiseasesNon syndromic hearing impairment with enlarged vestibular aqueductsIdentification of the second gene responsible for isolated hearing impairment with enlarged vestibular aqueducts -GenOmics 2017 - 1
2017Caroline NAVAParisFoundation For Rare DiseasesEpilepsy
Dravet syndrome
Identification of novel genes responsible for Dravet syndrome -GenOmics 2017 - 1
2017Veronique PAQUIS-FLUCKLINGERNiceFoundation For Rare Diseases Mitochondrial disordersIdentification of new genes and possible de novo mutations in early-onset mitochondrial disorders -GenOmics 2017 - 1
2017Veronique PINGAULTParisFoundation For Rare DiseasesWaardenburg syndrome type 2Molecular bases of Waardenburg syndrome type 2 -GenOmics 2017 - 1
2017Stephane SavaryDijonFoundation For Rare DiseasesX-linked adrenoleukodystrophy and Acyl-CoA Oxidase deficiency (peroxisomal leukodystrophies)Novel CRISPR-mediated mutant microglial cell models to better understand the physiopathogenesis of peroxisomal leukodystrophies and identify novel therapeutic targets by NGS RNAseq -GenOmics 2017 - 1
2017Capucine TROLLETParisFoundation For Rare DiseasesOculopharyngeal muscular dystrophyLong and small non coding RNA in oculopharyngeal muscular dystrophy -GenOmics 2017 - 1
2017François VIALARDParisFoundation For Rare DiseasesAzoospermiaIdentification and characterization of gene alterations in patients with a spermatogenesis maturation arrest -GenOmics 2017 - 1
2017Stephane VIVILLEStrasbourgFoundation For Rare DiseasesSpontaneous ovarian hyperstimulation syndrome (sOHSS)Exome sequencing in a consanguineous family with spontaneous ovarian hyperstimulation cases with unknown triggers -GenOmics 2017 - 1
2017Arturo LONDONO-VALLEJOParisFoundation For Rare DiseasesHoyeraal-Hreidarsson syndrome
Primary pulmonary fibrosis
Dyskeratosis congenita
RNA partitioning in RTEL1-associated Hoyeraal-Hreidarsson syndrome -GenOmics 2017 - 2
2017Pascale QUIGNONRennesFoundation For Rare DiseasesEpilespyWhole genome sequencing of dogs affected by idiopathic epilepsy as genetic models for human epilepsies -GenOmics 2017 - 2
2017Nicolas CHASSAINGToulouseFoundation For Rare DiseasesMicrophthalmia/anophthalmiaANALYSIS OF REGULATORY GENE SEQUENCES IN MICROPHTHALMIA/ANOPHTHALMIA -GenOmics 2017 - 2
2017SANDRINE PASSEMARDParisFoundation For Rare DiseasesPrimary microcephalies:
MicroCephaly Primary Hereditary, microcephalic dwarfism (Seckel syndrome / MOPD / Meyer Gorlin syndrome), microcephaly and chorioretinopathy
MICRO-WGS: Identifying genes responsible for primary microcephaly -GenOmics 2017 - 2
2017Arthur SORLINDijonFoundation For Rare DiseasesHypomelanosis of Ito, Linear Whorled Nevoid Hypermelanosis, and other mosaic development disorders with skin pigmentary anomaliesDeciphering the genetic basis of mosaic development disorders with skin pigmentary anomalies -GenOmics 2017 - 2
2017Gaetan LESCALyonFoundation For Rare DiseasesEpilepsy
West syndrome
Searching for the genetic basis of West syndrome with favorable outcome -GenOmics 2017 - 2
2017Pauline ARNAUDParisFoundation For Rare DiseasesMarfan syndrome
Familial Thoracic Aortic Aneurysm and Dissection
Identification of new genes involved in Marfan syndrome and Familial Thoracic Aneurysm and Dissection by WES and WGS approaches -GenOmics 2017 - 2
2017Betty GARDIENantesFondation Les Ailes / KiwanisHereditary erythrocytosis (HE)Whole genome sequencing of patients with hereditary erythrocytosis -GenOmics 2017 - 2
2017Nicolas RAMOZParisFoundation For Rare DiseasesAnorexia nervosa dominant form, eating disorders, psychiatric disordersCOMBINING HIGH THROUGHPUT SEQUENCING APPROACHES TO DEFINE THE GENETIC BASES OF DOMINANT FAMILIAL FORMS OF ANOREXIA NERVOSA -GenOmics 2017 - 2
2017Alexandre BACQParisFoundation For Rare DiseasesEpilepsyIdentification of novel pathogenic mechanisms involved in DEPDC5-related epilepsy and SUDEP. -GenOmics 2017 - 2
2017Jean MULLERStrasbourgFoundation For Rare DiseasesBardet-Biedl syndrome
Identification of genes and pathways implicated in families affected with a ciliopathy. -GenOmics 2017 - 2
2017Veronique PAQUIS-FLUCKLINGERNiceFoundation For Rare DiseasesMitochondrial diseasesIdentification of new genes responsible of mitochondrial disorders by RNA sequencing -GenOmics 2017 - 2
2017Jean-Jacques FEIGEGrenobleFoundation For Rare DiseasesHHT: Hereditary Haemorrhagic Telangiectasia (Rendu-Osler-Weber disease)
PAH: Pulmonary Arterial Hypertension
HHTreat: new drugs for the treatment of HHT patientsRendu-Osler disease is a rare genetic disorder characterized by vascular fragility leading to profuse nosebleeds, telangiectasias (small pockets of blood on the mucous membranes) and, at a more advanced stage, arteriovenous malformations responsible for heart failure. Only surgical or palliative treatments currently exist for this disabling disease. In 90% of cases, patients carry a mutation in the ACVRL1 or ENG genes, which code for receptors present in vascular cells. Our team has identified the physiological ligands of these receptors (BMP9 and BMP10) and developed cell-based assays to characterize
the functional consequences of these mutations. Building on this work, we now aim to identify new drug candidates for this disease by screening a bank of pharmaceutical compounds already on the market for other indications.
High throughput screening 2017
2017Johann BOHMIllkirchFoundation For Rare DiseasesTubular aggregate myopathy (TAM)A high-throughput screen to identify compounds antagonizing tubular aggregate myopathyMuscle diseases affect children and adults in all populations, and are potentially lethal. There is no therapy for a majority of these myopathies, which represents a considerable burden for patients and their families. Our team has identified the genetic causes of tubular aggregate myopathy (TAM), which involves muscle weakness, cramps and pain, and we have discovered that this disease stems from a calcium imbalance in the muscle. Calcium plays a vital role in normal muscle function, and aberrant calcium homeostasis is observed in various muscle diseases. We aim to test the potential of approved drugs to reverse cellular alterations and - in perspective - restore muscle function in an animal model of TAM. Through this project, we aim to pave the way for the development of a pharmacological treatment for TAM and other calcium-related myopathies.High throughput screening 2017
2017Marie-Odile FAUVARQUE MARRASGrenobleFoundation For Rare DiseasesCushing's diseaseTargeting USP8 in Cushing's diseaseCushing's disease is a rare disorder in which pituitary micro-tumors produce
excess adrenocorticotropic hormone (ACTH) and consequent hypercortisolism. This can lead to obesity, brittle skin, cardiovascular disease, depression and reduced fertility.
depression and reduced fertility. The first-line treatment is transphenoidal surgery, which results in a high remission rate for 64-90% of patients. However, a significant percentage of pituitary adenomas recur, and not all tumors are operable. Recently, mutations in the USP8 protease have been found in patient micro-tumors. These mutations cause constitutive enzyme activity and increased ACTH secretion. The project aims to provide specific USP8 inhibitors with satisfactory medicinal properties in order to develop a personalized treatment for Cushing's disease.
High throughput screening 2017
2017Jean-Vianney BARNIERParisFoundation For Rare DiseasesIntellectual disabilityFirst mutation in the auto-inhibitory domain of the PAK3 gene associated with ID.Advances in human genetics have made a decisive contribution to our understanding of psychiatric neurodevelopmental disorders. However, mutations in the same gene can lead to different
different pathologies, without the reason being understood. Understanding the relationship between a mutation, its functional effects and clinical signs is essential for proposing therapeutic strategies. We have identified a new mutation associated with mental retardation in a gene coding for a kinase, a mutation which does not destroy enzymatic activity. We aim to understand the biochemical defects induced by this mutation in vitro and in cells. We would like to have the corresponding mouse model to link these dysfunctions to behavioral and memory abnormalities, as well as to synaptic defects and clinical signs in patients. The results obtained should enable us to propose therapeutic strategies.
Mouse models 2016
2017Jean-Jacques BOFFAParisFoundation For Rare DiseasesIdiopathic nephrotic syndromePathophysiological role of Isthmin-1 in idiopathic nephrotic syndromeIdiopathic nephrotic syndrome (INS) is a kidney disease that affects both children and adults.
unknown mechanisms. We have discovered the involvement of isthmine-1 (ISM-1), whose role in renal
in renal pathophysiology. We have shown physiological expression in podocytes (renal cells and target of NIS), but above all strong de novo expression by circulating leukocytes of adults and children suffering from NIS. Our aim is to develop a strain of transgenic mice to study the pathophysiological role of ISM-1 in INS. We hypothesize that circulating ISM-1 acts as a permeability factor and induces proteinuria. These mice would overexpress ISM-1 in leukocytes and mimic human INS. Our results have already led to the filing of a patent, and we are looking forward to identifying a therapeutic target for SNI.
Mouse models 2016
2017Anne DEBANTMontpellierFoundation For Rare Diseasesneurodevelopmental disorders
Intellectual disability (ID)
Contribution of de novo mutations in the trio gene in intellectual disability: development of a trio knock-in mouse model mimicking the human diseaseThe integrity of synaptic activity is essential for proper brain function. Alterations in synaptic function are implicated in diseases such as autism and mental retardation. Recent data have revealed new mutations in these patients, which could alter the function of the affected genes and thus contribute to the development of the disease. We are working on the RhoGEF Trio, which plays a fundamental role in neuronal development. Mutations in this gene have been identified in patients suffering from autism and mental retardation. The aim of the project is to understand how mutations in this gene affect its function and how they cause mental retardation. We aim to develop a mouse model that mimics the mental retardation caused by mutations in the trio gene, to better understand the pathophysiology of the disease and lead in the long term to the identification of therapeutic targets.Mouse models 2016
2017Juliette GODINIllkirchFoundation For Rare DiseasesMalformation of cortical development - microcephaly - intellectual disabilitiesUnderstanding the roles of tRNAs modifications in cerebral corticogenesis through the investigation of an ADAT3 knock-in modelTransfer RNAs (tRNAs) are key molecules in protein synthesis. In order to be functional, these tRNAs undergo a dozen or so modifications. We have recently established a link
between the presence of certain modifications and the ability of neural stem cells to generate
neurons. In addition, mutations in several modifying enzymes have been associated with neurodevelopmental pathologies in humans. How do mutations in these enzymes lead to brain malformations? We will take a candidate approach and characterize the developmental functions of a tRNA-modifying enzyme, ADAT3, which, when mutated, leads to microcephaly (smaller brain size). We will evaluate the functions of ADAT3 altered by the mutations found in patients. This study will lead to a better understanding of the fundamental causes of neurodevelopmental disorders, and to the discovery of new therapeutic targets.
Mouse models 2016
2017Denis HERVEParisFoundation For Rare DiseasesADCY5-related dyskinesiaA mouse model for studying pathophysiological mechanisms of ADCY5-related dyskinesiaParoxysmal dyskinesias are rare diseases characterized by episodes of involuntary abnormal movements, which are very disabling in some patients. Recently, geneticists have found that the disease results from mutations in a gene called ADCY5 in certain patients. This discovery
led to the creation of a group of ADCY5-associated dyskinesia sufferers, around one of the first patients to be diagnosed ( website). The functions of the ADCY5 gene are well known to scientists, but the consequences of its mutations are still unknown. The aim of the project is to create a mouse with a mutation exactly equivalent to that found in patients heavily affected by the disease, in order to discover the altered biological mechanisms in neurons. We will investigate whether mutant mice show movement disorders similar to those of patients, and we will test drugs likely to reduce motor abnormalities.
Mouse models 2016
2017Pascal HOUILLIERParisFoundation For Rare DiseasesFamilial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC)A Claudin 16-knock-in mouse as a model of Familial hypomagnesemia with hypercalciuria and nephrocalcinosisA very rare genetic disease of recent discovery, "familial hypomagnesemia with hypercalciuria
hypomagnesemia with hypercalciuria and nephrocalcinosis" (FHHNC), results in decreased blood magnesium concentration
Calcification of the kidneys and renal failure may lead to dialysis. There is currently no specific treatment for this disease. It is linked to the loss of function of a protein (claudin 16) which serves as a cell-cell junction in a part of the kidney specifically involved in the reabsorption of magnesium and calcium. The mouse model used to study this disease is not fully representative of human pathology. We therefore aim to create a genetically modified mouse model, carrying a human genetic mutation for this disease, enabling us to better understand it and test new treatments.
Mouse models 2016
2017Metodi METODIEVParisFoundation For Rare Diseasesmitochondrial diseases; Leigh syndrome including French-Canadian Variant (LSFC).A mouse model to understand the pathophysiology and tissue-specificity of mitochondrial disease caused by mutations in the RNA stability factor LRPPRC.Mitochondrial diseases are incurable, often very severe, and affect 1 in 5000 individuals. They are caused by mutations in different genes and lead to a wide variety of clinical symptoms. To better understand and treat these diseases, we need to create better models to study disease progression and tissue specificity. We will create mice expressing a deleterious mutation in the LRPPRC gene, involved in mitochondrial RNA metabolism. This gene has already been associated with
lactic acidosis, and sometimes liver disease and (cardio)myopathy. In-depth studies in different tissues will enable us to better understand how mutations in the LRPPRC gene lead to mitochondrial diseases in humans. Mouse models will also be used to develop new treatments for this and other severe diseases caused by mitochondrial dysfunction.
Mouse models 2016
2017Benoit MIOTTOParisFoundation For Rare DiseasesMeier-Gorlin SyndromeStudy of a mouse model of Meier-Gorlin Syndrome based on a mutation in the conserved BAH domain of ORC1Meier-Gorlin syndrome is a rare disorder characterized by growth failure from the earliest stages of development in utero. Patients are small in stature, with underdeveloped ears and kneecaps. Mutations in several genes encoding factors essential for the initiation
DNA replication are responsible for the syndrome. Mutations causing the most severe phenotype alter the function of the ORC1 gene. The most recurrent ORC1 mutation results in the substitution of glutamine for arginine 105 at the protein level. We propose to build a mouse model containing this mutation. This model will enable us to study the developmental processes affected by the ORC1 mutation, such as signaling pathways and various molecular processes. Taken together, these data will provide a better understanding of the events leading to the disease, and enable us to propose possible therapeutic targets in the future.
Mouse models 2016
2017Stephane NEDELECParisFoundation For Rare DiseasesSpinal muscular atrophy, lower extremity-predominant, 2, AD
Development and characterization of preclinical Human and Mouse models of Spinal Muscular Atrophy to determine the mechanisms of selective motor neuron impairmentsSpinal muscular atrophies are rare neurodevelopmental genetic diseases characterized by selective degeneration of certain neurons, leading to paralysis and sometimes death. Understanding the mechanisms that protect certain neurons could lead to the discovery of new therapeutic avenues. We are therefore studying the cellular and molecular bases underlying the resistance
or sensitivity of particular groups of motor neurons in a severe infantile case associated with the BICD2 gene and characterized by selective damage to neurons innervating the legs. We have succeeded in generating these lumbar neurons in vitro from patient biopsies. We will study their characteristics in detail to determine what makes them more fragile than other neuronal populations. The study of a mouse mimicking the patients' genetic defect will be essential to complete our in vitro data.
Mouse models 2016
2017Miria RICCHETTIParisFoundation For Rare DiseasesCockayne syndromeA mouse model for Cockayne syndromeCockayne syndrome (CS) is a rare disease characterized, like other syndromes, by sensitivity to light (UV rays), but also by premature aging and neurodegeneration.
The mouse model of mutation of the same proteins as in humans (CSA and CSB) does not recapitulate the disease, except for UV sensitivity. We have recently discovered a specific defect in SC,
which is independent of UV sensitivity, and consists in the degradation of an important protein in mitochondria, the energy-producing organelles of cells. This results from overexpression of the protease, HTRA3, which degrades other proteins. We have reversed the altered parameters in the cells of CS patients, opening up therapeutic strategies that do not currently exist. Our project is to over-express HTRA3 in mice to trigger premature aging and neural degeneration, in order to study them and test treatments.
Mouse models 2016
2017Laurent SCHAEFFERLyonFoundation For Rare DiseasesNeuromuscular disorders affecting the neuromuscular junctionLight up the neuromuscular junction to monitor muscle innervationNeuromuscular diseases encompass a wide range of pathologies affecting muscles, the motor neurons that control them and/or their meeting point, the neuromuscular junction (NMJ). Loss of motor neurons inevitably results in impaired muscle contraction. Unfortunately, assessing the state of communication between neurons and muscles in
mice models of neuromuscular disease is difficult and requires specialized electrophysiological and pathological methods. To circumvent these difficulties, we propose to develop a mouse that will greatly simplify and standardize the state of nerve-muscle communication by introducing a fluorescent sensor of this communication into the muscle. This will greatly facilitate quantitative analysis and monitoring of the innervation status of an entire muscle.
Mouse models 2016
2017Jacques YOUNGParisFoundation For Rare DiseasesSevere hyperandrogenism and oligomenorrheaKI mouse model as a proof of concept for human hyperandrogenism, anovulation associated with activating LHCGR mutationOvarian and testicular function requires stimulation by two hormones, the gonadotropins (FSH and LH) secreted by a gland at the base of the brain, the pituitary gland. They act via receptors located in testicular and ovarian cells. In healthy individuals, these receptors do not function until puberty. Genetic abnormalities in the receptor genes can disrupt their function. In a patient with masculinization and high testosterone, we have discovered a very rare mutation which enables the receptor to function without the intervention of LH. We will reproduce this mutation in a female mouse to induce the same type of disease and gain a better cognitive understanding of ovarian function. This will enable us to demonstrate the responsibility of the mutation we have discovered, and to avoid confusing this disease with others with similar symptoms.Mouse models 2016
2017Pierre ANCETDijonFoundation For Rare DiseasesCongenital Giant NaevusStudy Congenital Giant Naevus: Psychology, Info-Com, Health, Transdisciplinary, EthicsGiant congenital nevus is a rare skin malformation characterized by giant moles on the body and/or face. They vary in complexion from reddish-brown to black, and may be smooth or covered with hairs or bumps. Repeated plastic surgery is generally proposed to prevent serious cancers, which occur in 5% of affected children, but to date there is no way of knowing how effective it is, or whether the benefits outweigh the risks. Thus, this research project focuses on the psychosocial consequences and ways to improve their repercussions.
We will study the challenges faced by:
1. parents: how did they feel when the nevus was discovered at birth? Were they well informed by the medical teams? How long did their diagnostic wandering last, and what was the effect on their relationship with the baby or the doctors?
2. children, teenagers and adults with a nevus: how do they feel about themselves and other people, whether face-to-face or on social networks?
Our approach will involve doctors, researchers in the human sciences (philosophy, psychology, communication) and professional representatives of French family associations. This interdisciplinary team will collaborate with another association whose aim is to offer workshops for
people with aesthetic disabilities, in particular giant nevi, using cognitive and behavioral compensation techniques already successfully tested for burns and other malformations.
A comic strip featuring a heroine visibly affected by a giant nevus will be one of the tools, and information will be disseminated via social networks and associations. Interviews and other analyses will be carried out before and after the workshops to assess their effectiveness.
Humanities and social sciences 5
2017Lionel DANYMarseilleFoundation For Rare DiseasesSystemic lupus erythematosusPsychosocial consequences of systemic lupus erythematosus: a study of patients and their spousesSystemic lupus erythematosus (SLE) is a rare chronic autoimmune disease (1/2000 population) which progresses in relapses interspersed with periods of remission. Most sufferers are young women of childbearing age. SLE has an impact on both married and family life (financial, emotional, relational and sexual conditions). What's more, the disease and its treatments can hamper the possibility of building a family project (pregnancy).
The aim of the Psy-LUP study is to investigate the repercussions of SLE on patients' social participation, i.e. on their ability to get involved in the various areas of daily life. The more active the lupus disease, and the more severe its complications, such as kidney damage, the greater the impact.
Our aim is to study how people with lupus and those close to them (spouses in particular) perceive lupus disease, how it fits into their life history, how they have adapted to the disease and what impact it has had on their social participation, social support and life as a couple.
The Psy-LUP study will be carried out in various care services, and by telephone interviews at home, with two main thrusts: (1) a questionnaire study with patients; (2) a qualitative research interview study with patients and their spouses.
All the data collected will be used to target interventions with 1) patients and their families, in terms of therapeutic education, psychosocial support and support groups (associations); 2) carers caring for people with SLE, so that they can integrate the challenges of patients' experiences into their care practice and their thinking about therapeutic strategies.
Humanities and social sciences 5
2017Agnes DUMASParisFoundation For Rare DiseasesCongenital adrenal hyperplasia, Isolated anorectal malformations or syndromic, Crohn's disease, Juvenile idiopathic arthritis, MucoviscidosisTransition Platforms: Understanding the Expectations of Parents of Young People with Rare DiseasesContext:
Young patients are faced with the transition of care from pediatrics to adult wards. Scientific recommendations all agree on the need for upstream preparation for the transition
and the need to involve adolescents and their parents. In this respect, several hospitals have recently built "transition platforms".
These platforms are designed to meet the needs of young patients first and foremost. There is currently no intervention aimed at parents. To improve care provision, it is essential to know what difficulties and expectations parents of young patients face.
-Characterize, in different medical and social contexts, the experience of transition, from the point of view of parents of young people with rare diseases;
-Identify parents' expectations of their child's care within a transition platform.
This is a qualitative study based on interviews with a sample of parents of young people cared for in the transition platforms of two hospitals in the Paris region. Interviews will also be conducted with representatives of associations involved in the platforms to benefit from their expertise. Observations will also be carried out in the platforms to understand how they operate.
Expected results:
The research will lead to a better matching of care and support provision to the specificities of
of rare diseases, and to the development of interventions entirely dedicated to parents. This will have a major impact not only on the two platforms involved in the project, but also on platforms under construction in other locations.
Humanities and social sciences 5
2017Stephanie MAZZALyonFoundation For Rare DiseasesNarcolepsy type 1Study of the academic and professional path of narcoleptic patientsType 1 narcolepsy is a rare, disabling chronic sleep disorder characterized by abnormal sleepiness and emotion-related muscle tone dips (cataplexy). It begins in childhood or young adulthood. Its symptoms are responsible for significant disability, and are often poorly understood by those around them. Other conditions are often associated with narcolepsy (depression, anxiety, obesity).
Few studies have examined the impact of narcolepsy on patients' educational and professional careers. Little is known about the handicap factors associated with the characteristics of the disease, and the determinants of patients' integration into society, even though this information could be used to inform patients, guide them in their choices of orientation, and act on certain critical factors.
The aim of the NarcoScol/NarcoVitae study is to take stock of the academic and professional career paths of narcolepsy patients in a large national population, and to analyze the determinants of these paths.
Patients will be recruited from reference/competence centers treating adults and children suffering from narcolepsy. They will be offered questionnaires as part of their usual
follow-up, as well as to related or unrelated control subjects. The following will be assessed: educational and professional background, use of available aids, quality of life, depression, sleepiness and, for patients, the severity of the disease. The study will also assess the financial impact of the disease on patients and society.
The NarcoScol/NarcoVitae study will 1) provide patients with better information to help them choose their career path, train and keep their jobs 2) set up specific actions to help them integrate into school and the workplace.
Humanities and social sciences 5
2017Maria POPA-ROCHStrasbourgFoundation For Rare DiseasesEhlers-Danlos syndrome,
Ondine syndrome
Juvenile arthritis
Rare Invisible Disease and Schooling of ChildrenThe aim of this research program is to promote school inclusion for children with Ehlers-Danlos, Ondine and juvenile arthritis syndromes. Indeed, parents who are members of partner associations and clinicians who see these children in consultation have told us about the difficulties the children encounter, which are barriers to their development at school. Very often, the testimonies reveal resistance on the part of the teaching staff and attitudes that could be detrimental to learning: as the disability is not visible and the difficulties unrecognized, teachers find themselves worried and feel uncomfortable when faced with these different pupils.
This program, conducted in collaboration with parents, doctors and psychology researchers, aims to show how the success of young people with these syndromes can depend on teachers. We will measure teachers' attitudes (conscious or unconscious) and the cognitive abilities of students with these rare diseases and their non-diseased peers. Our hypothesis is that if these young people do less well at school than other pupils, it's not a question of their objective level of intelligence and reasoning, but depends on how they are perceived by their teachers.
These results will enable us to develop a specific training program for teachers in order to
reduce their resistance and a priori attitudes towards pupils with rare and little-known diseases. This training will be tested experimentally before being included in the training program for future teachers to improve the benefits of school inclusion for children with invisible disabilities.
Humanities and social sciences 5
2017Virginie POSTALBordeauxFoundation For Rare DiseasesPrader Willi syndromeCommunication in Prader-Willi syndrome: study of emotional control related to behavioural disorders, their daily repercussions and examination of innovative therapiesPrader Willi syndrome (PWS) is a rare (1 in 25,000 births) and complex genetic disease
characterized by mild to moderate intellectual retardation, obesity and behavioral problems.
behavioral problems. It leads to difficulties in social integration, first at school and then at work (only 4% of PW adults in France live alone). Integration into the mainstream or into a work-based support service, as well as day-to-day management by families, is difficult due to frequent behavioral problems. Over 80% of PWS patients suffer from temper tantrums.
In view of these difficulties, and their repercussions on families and carers (stress, burden, etc.), identifying the factors that explain these disorders would enable us to gain a better understanding of the syndrome as a whole, and to tailor treatment more effectively. Proposing new therapeutic avenues is a major challenge in this syndrome, for which there is currently no drug treatment.
The aim of the PRACOM (PraderWilli Communication) project is to identify and characterize emotional functioning disorders, in particular those linked to anger, and their behavioral consequences; to situate them in their environmental contexts (frequency, cause, consequences on well-being and parental, school or professional relationships); and to propose innovative therapeutic approaches aimed at improving these behavioral disorders.
Various questionnaires and semi-directive interviews will be administered to children and adults with PWS, their families and professionals working in care facilities. At the end of these assessments, 3 innovative approaches will be evaluated to offer new therapeutic avenues, which could be extended to pathologies with similar disorders.
Humanities and social sciences 5
2017Sebastien RUFFIEPointe-à-PitreFoundation For Rare DiseasesSickle cell diseaseSickle cell disease, neurocognitive disorders and social participationSickle cell disease is the most common genetic disorder in France.
to reduce morbidity and mortality. In Guadeloupe, systematic screening
from birth encourages early medical care, combined with psychological and social follow-up.
Sickle-cell anemia in children can lead to neurological complications, including stroke, which can develop with or without clinical signs. A major risk associated with these strokes is the impact on general intellectual functioning and
neuropsychological disorders affecting intellectual functioning, executive and attentional functions. The aim of this project is to study the influence of these neurocognitive disorders on the participation of children and adolescents with sickle cell disease (aged 6 to 16) in Guadeloupe.
neurocognitive disorders on social participation not previously explored, in contrast to the well-documented
well-documented negative impact of sickle cell disease on quality of life. The results of social participation assessments will be analyzed according to the nature of neuropsychological disorders, using a transdisciplinary approach. Neuropsychological disorders will be investigated by the clinical psychologists and neuropsychologists regularly involved in the care of these patients, using the usual appropriate tests. To assess their social participation, methods adapted to detect the obstacles and facilitators involved in the social integration of individuals will be used (MHAVIE and MQ,). Semi-structured interviews will complete the qualitative data collection. Expected results include
understanding the impact of neurocognitive disorders on the personal and/or environmental difficulties encountered by these patients in their social participation.
Humanities and social sciences 5
2018Stephane BEZIEAUNantesFoundation For Rare DiseasesIntellectual disabilityTrio-based whole-genome sequencing of patients with syndromic and non-syndromic moderate or severe intellectual disability -GenOmics 2018 - 1
2018Clement CARREParisFoundation For Rare DiseasesIntellectual Disability (ID)
Non-syndromic X-linked Intellectual Disability (NSXLID)
tRNA Fragments & RNA methylation detection for functional diagnostic in Intellectual Disability -GenOmics 2018 - 1
2018Marie-Christine CHABOISSIERNiceFoundation For Rare DiseasesFrasier syndrome Identification of the Genetic Network Leading to Frasier Syndrome and other Disorders of Sexual Development -GenOmics 2018 - 1
2018Mireille COSSEEMontpellierFoundation For Rare DiseasesMyopathies and Muscular dystrophiesEvaluation of a Whole Genome and RNA-sequencing strategy to identify the molecular bases of unsolved myopathies and muscular dystrophies -GenOmics 2018 - 1
2018Caroline KANNENGIESSERParisFoundation For Rare DiseasesPleuroparenchymal fibroelastosis
Pulmonary fibrosis
Identification of new genes implicated in Pleuroparenchymal fibroelastosis -GenOmics 2018 - 1
2018Stanislas LYONNETParisFoundation For Rare DiseasesMayer-Rokitansky-Kuster-Hauser syndromeDeciphering the molecular mechanisms leading to Mayer-Rokitansky-Kuster-Hauser syndrome -GenOmics 2018 - 1
2018Frederique MAGDINIERMarseilleFoundation For Rare DiseasesFacio Scapulo Humeral Dystrophy (FSHD)
Bosma Arhinia and microphthalmia (BAMS)
Identification of genes and regions regulated by the SMCHD1 chromatin-associated factor in Facio-Scapulo-Humeral Dystrophy (FSHD) and Bosma Arhinia and Microphtalmia Syndrome (BAMS) -GenOmics 2018 - 1
2018Anne PHILIPPEParisFoundation For Rare DiseasesNon syndromic autism spectrum disordersWhole exome sequencing in non-syndromic autism spectrum disorders -GenOmics 2018 - 1
2018Helene PUCCIOIllkirchFoundation For Rare DiseasesFriedreich AtaxiaIdentification of pathological mechanisms underlying proprioceptive neurons dysfunction and cell death in Friedreich Ataxia -GenOmics 2018 - 1
2018Florent SOUBRIERParisFoundation For Rare DiseasesPrecapillary Pulmonary arterial hypertensionSearch for new genes in familial pulmonary hypertension by Whole Genome Sequencing -GenOmics 2018 - 1
2018Stephane VIVILLEStrasbourgFoundation For Rare DiseasesFemale infertilityExome sequencing in consanguinous families in the quest of genes implicated in oocyte maturation arrest -GenOmics 2018 - 1
2018Caroline LE GUINERNantesFoundation For Rare DiseasesDuchenne Muscular DystrophyGene therapy for the cardiac disease in Duchenne Muscular Dystrophy: Definition of the optimal mode of delivery to transduce the heart of nonhuman primates using a rAAV9 vector -Preclinical research 2017
2018Laurent STORMELilleFoundation For Rare Diseases Congenital diaphragmatic herniaOptimization of intact cord resuscitation in newborn lambs with congenital diaphragmatic hernia -Preclinical research 2017
2018Gabriel RAHMIParisFoundation For Rare DiseasesEsophageal atresia
Anastomotic fistulas
Fistula therapy by extracellular vesicles into thermoreversible hydrogels: tackling a complication of esophageal atresia reparative surgery -Preclinical research 2017
2018Laurent TIRETParisFoundation For Rare DiseasesCentronuclear myopathies, Myotubular myopathies, Fiber-size disproportion myopathies, Mitochondrial myopathiesEstablishment and characterization of a humanized canine DNM2 colony dedicated to validate efficient treatments in mice -Preclinical research 2017
2018Carolina BAEZA-VELASCOParisFoundation For Rare DiseasesHypermobile Ehlers-Danlos syndromeActivity patterns of people with hypermobile Ehlers-Danlos syndrome: associated factors and decision making
Ehlers-Danlos syndromes (EDS) are a heterogeneous group of inherited connective tissue disorders. Hypermobile EDS (hEDS) is the most common form, accounting for 80-90% of cases of
SED. The manifestations of hEDS are multi-systemic due to the wide distribution of collagen in the body. Pain is nevertheless the most frequent symptom. The variety and accumulation of pain
and their long duration make hEDS a potentially very disabling pathology. Studies show severe functional impairment in hEDS, determined mainly by pain and fatigue. This leads to a reduction in patients' ability to hold down gainful employment, perform household chores and engage in social activities. In this sense, it is necessary to identify the factors contributing to functional decline in hEDS to manage the personal and economic impact that generates this pathology. One of the key factors in the overall functioning of chronic pain patients is their relationship to activity (activities of daily living and the way they carry them out). Three major patterns of activity have been observed: avoidance, persistence and modulation. These patterns may be responsible for perpetuating pain and disability. They have been studied in a variety of pain-related pathologies, enabling us to propose appropriate treatments to help restore patients' function by promoting the right mix of activities. However, no study has explored the relationship between activity and people with hEDS.
This study explores patients' dysfunctional activity patterns, associated factors, the link between patterns and functional outcome, and patients' decision-making processes regarding activity. The results will help to better target rehabilitation strategies.
Humanities and social sciences 6
2018Delphine HERONParisFoundation For Rare DiseasesIsolated corpus callosum agenesisDecision-making processes of couples facing prenatal diagnosis of isolated agenesis of the corpus callosum
The aims of the study are: (1) to study and describe the effects of decision-making in couples faced with major uncertainty about the child's future (risk of disability) during pregnancy; (2) to study the experience and psychological impact of couples regarding their decision to continue or terminate pregnancy; (3) to identify the needs of those concerned, in order to reassess practices and improve the care pathway currently on offer. We have chosen as an example the case of prenatal diagnosis of agenesis of the corpus callosum of isolated appearance, which constitutes a paradigm of this situation of uncertainty, since for the same anomaly (ACC), 75% of children will have normal development and 25% will have a neurological handicap (severe in 5 to 10% of cases), leading parents to make a decision based on statistics. We propose to meet 50 couples divided into 2 groups: (G1) 25 who have decided to continue the pregnancy and (G2) 25 who have decided to stop it. The proposal to enter this research protocol will be made a few months after the birth (whatever the outcome), in order to better identify the factors involved in this decision, their feelings about it, and the couples' experiences afterwards. The interviews will also be accompanied by the use of scales to take into account the emotional state of each individual, as well as the conjugal bond and its particularities.
and its particularities. This research will lead to a better understanding of the factors that lead parents to make
decision to continue or terminate a pregnancy, and can then be extended to other situations of prenatal uncertainty. These factors will lead to the implementation of better support for these couples, to better meet their needs and support them in their decision-making process, through concrete measures applicable to the care offered.
Humanities and social sciences 6
2018Charlotte JACQUEMOTParisFoundation For Rare DiseasesHungtingtonUsing language as a marker for Huntington's disease to improve management and follow-up
Huntington's disease is an incurable genetic and neurodegenerative disorder. It affects young adults (aged 35-45) and causes motor, cognitive and psychiatric disorders. Although little-known, language disorders are among the first cognitive problems to appear. They reduce patients' ability to communicate, have a major impact on their personal and professional lives, and gradually lead to social exclusion. To date, there is no standardized protocol for assessing language disorders in Huntington's disease. However, the assessment stage is crucial to proposing appropriate treatment and rehabilitation. It enables us to set rehabilitation objectives and determine the therapeutic approaches best suited to the patient. To remedy this shortcoming, our project is to characterize patients' language disorders and develop a language assessment protocol to improve
and propose effective rehabilitation. We will focus on three essential parameters of communication which, when deficient, are highly disabling for patients: intelligibility (phonetics), words (lexicon), and the ability to use humor and irony (pragmatics). For each parameter, we will obtain a score indicating whether or not a deficit exists. The secondary objective is to use these different scores to detect the first signs of the disease as early as possible. Indeed, treatments are more likely to be effective if delivered at the very beginning of the disease, and it is therefore crucial to have "markers" of this phase. This project will be carried out in collaboration with the Huntington France Association, and will involve researchers from the "Language" team
of the NeuroPsychologie Interventionnelle laboratory, experts in the cognitive disorders of Huntington's disease.
Humanities and social sciences 6
2018Celine LANCELOTAngersFoundation For Rare DiseasesTurner syndromeImpact of social and affective cognition skills on relationship and social adjustment difficulties in adolescent girls with Turner syndrome
Turner syndrome (TS) is a rare chromosomal disorder linked to the complete or partial absence of an X chromosome.
of an X chromosome, affecting around one in every 2,000 female newborns. While the medical consequences are well described and benefit from appropriate treatment, understanding of the cognitive and socio-cognitive specificities associated with complaints about establishing or maintaining harmonious social relationships is less well developed, particularly in children and adolescents.
Some girls with TS may complain of difficulties in making friends, understanding the emotions and intentions of others, and controlling their own emotions. These difficulties in social and affective cognition can contribute to the emergence of social withdrawal, which can have repercussions on their psycho-emotional well-being. The aim of this project is to identify functional and dysfunctional cognitive and social-cognitive abilities in girls with TS that may account for the difficulties in social interaction and adjustment reported by some of them. To this end, 35 participants with TS aged between 10 and 16 years 11 months and 35 control participants matched according to age and parents' level of education will undergo clinical and experimental tests evaluating
cognitive functioning, social cognition and affective cognition, as well as questionnaires exploring psycho-affective aspects and social skills. In order to examine the specificity of the cognitive, social and affective profile of patients with ST, a second control group consisting of children and adolescents with idiopathic isolated growth hormone deficiency with normal cranial MRI will be created. We assume that complaints concerning social functioning will be explained mainly by difficulties in affective cognition.
Humanities and social sciences 6
2018Bruno QUINTARDBordeauxFoundation For Rare DiseasesAlbinismBiopsychosocial determinants of dyadic adjustment to illness in albino subjects and their close circle: a mixed qualitative and quantitative approach
Oculocutaneous Albinism [OCA] is a rare disease with various symptoms (depigmentation,
visual deficit, sun exposure disorders). This displaying disease has social (stigmatization, withdrawal) and psychological consequences for the AOC subject and those around him/her (adaptation disorders, altered quality of life [QoL]). To date, no study has jointly explored the experience of COA in the subject and his or her close caregivers (family and non-family).
- To explore the psychosocial impact (stigmatization, QoL, emotional state) of albinism on the AOC subject and his/her close relative (parent or spouse);
- To compare the way in which the AOC subject and his/her close relative (parent or spouse) experience the disease, and to see whether or not there is convergence in this experience;
- at the level of non-family caregivers (caregivers, GENESPOIR albinism association), assess the relevance of the proposed interventions, given the specific needs of the AOC patient and his/her relative.
- 150 pairs (AOC subject + parent or spouse) recruited by GENESPOIR and the skin CRMRs of Bordeaux, Necker and Strasbourg. Protocol evaluating :
- various contextual, medical and personal factors associated with: QoL, emotional state and degree of perceived stigma ;
- 30 interviews with family pairs (AOC subject/spouse or parent) and 30 interviews with non-family carers (15 carers; 15 GENESPOIR members), to explore representations of the disease, its consequences and needs in terms of medical and associative support.
This study is original in that it combines an approach focused partly on the discourse of the AOC subject, but also on that of his or her relatives.
It should enable us to gain a better understanding of the complexity of interactions between the various partners involved in COA, and to better adapt medical and associative intervention methods to the specific needs of patients and their relatives (parents or spouses).
Humanities and social sciences 6
2019Piotr TOPILKOParisFoundation For Rare DiseasesNeurofibromatosis type 1 (Recklinghausen disease)Identification of markers of the cells at the origin of cutaneous Neurofibromatosis type 1 tumours and deciphering the molecular mechanisms responsible for malignant transformation of plexiform neurofibromas -GenOmics 2018 - 2
2019Sadia SAEEDLilleFoundation For Rare DiseasesSevere early onset obesityIdentification of new genes and rare variants implicated in monogenic severe obesity in children from a consanguineous population. -GenOmics 2018 - 2
2019Carole ESCARTINFontenay aux RosesFoundation For Rare DiseasesHuntington's diseaseMicroglial cells: the third element for mutant Huntingtin clearance in Huntington's disease? -GenOmics 2018 - 2
2019Arnaud DUPUISStrasbourgFoundation For Rare DiseasesPlatelet delta storage pool deficiency Looking for gene(s) responsible for non-syndromic platelet delta storage pool deficiency. -GenOmics 2018 - 2
2019Clémence VANLERBERGHELilleFoundation For Rare DiseasesFibular hemimelia
Fuhrmann syndrome
Santos syndrome
FATCO (Fibular Aplasia - Tibial Campomelia - Oligosyndactyly)
FFU complex (Femur - Fibula - Ulna)
Deciphering the genetic basis of fibular hypoplasia/agenesis -GenOmics 2018 - 2
2019Céline GAUCHERParisFoundation For Rare Diseasesamelogenesis imperfecta
dentinogenesis imperfecta
dentin anomalies

WES for non-syndromic dental hard tissues anomalies: ExoDent
-GenOmics 2018 - 2
2019Anne LETESSIERParisFoundation For Rare DiseasesMEIER-GORLIN SYNDROME 1; MGORS1 (MGS; OMIM#224690; ORPHA:2554)Molecular analysis of Meier-Gorlin Syndrome type 1: consequences of ORC1 mutation on chromatin organization and gene expression. -GenOmics 2018 - 2
2019Nadine CERF-BENSUSSANParisFoundation For Rare DiseasesVery early onset inflammatory bowel diseases and congenital diarrheas Whole genome sequencing in Very Early Onset- IBD and related intestinal disorders -GenOmics 2018 - 2
2019Aurélien TRIMOUILLEBordeauxFoundation For Rare DiseasesOculo-auriculo vertebral spectrumFurther delineation of molecular bases of Oculo-Auriculo-Vertebral Spectrum -GenOmics 2018 - 2
2019Isabelle PERRAULTParisFoundation For Rare DiseasesLeber congenital amaurosis (LCA, MIM204000) and other early-onset severe retinal dystrophies (EOSRD) are leading cause of incurable blindness in childhood.
Sensorineural hearing loss (SHL)
2019Michèle STUDERNiceFoundation For Rare DiseasesHereditary congenital facial paresis (HCFP3) (OMIM #614744) Unravelling the Genetic Pathways Leading to Hereditary Congenital Facial Palsy and Associated Hearing Loss -GenOmics 2018 - 2
2019Sandrine BARBAUXParisFoundation For Rare DiseasesThe Sertoli Cell Only Syndrome (SCOS).GENETIC CAUSES OF A RARE FORM OF INFERTILITY, THE SERTOLI CELL ONLY SYNDROME -GenOmics 2018 - 2
2019Suzanne LESAGEParisFoundation For Rare DiseasesEarly-onset Parkinson's disease (Orphanet ORPHA:2828)Whole genome sequencing in a North African consanguineous family with an early-onset Parkinson's disease -GenOmics 2018 - 2
2019Pascal AMEDROMontpellierGIRCI SOHO / Fondation Maladies RaresHereditary heart disease Quality of life and physical activity in children with hereditary rhythmic disease or cardiomyopathy of genetic origin: a multicenter prospective cross-sectional controlled study. -GIRCI SOHO 2019
2019Yves DULACToulouse GIRCI SOHO / Fondation Maladies RaresMARFAN syndromeEffect on quality of life of a therapeutic education program in patients with Marfan syndrome: an observational, prospective, multicenter study -GIRCI SOHO 2019
2019Guillaume MARTIN-BLONDELToulouse GIRCI SOHO / Fondation Maladies RaresProgressive multifocal leukoencephalopathy (PML), infectious diseases, Lymphocyte expression of immune checkpoint molecules during progressive multifocal leukoencephalopathy (PML). -GIRCI SOHO 2019
2019Cyril GOIZETBordeauxGIRCI SOHO / Fondation Maladies RaresNeurogenetic diseasesThe contribution of Oxford Nanopore next-generation high-throughput sequencing to the diagnostic strategy for neurogenetic diseases -GIRCI SOHO 2019
2019Cecilia MARELLIMontpellierGIRCI SOHO / Fondation Maladies RaresFriedreich's ataxiaCharacterization and study of the role of GAA repeat interruptions in the severity of Friedich's Ataxia
2019Eulalie LASSEAUXBordeauxGIRCI SOHO / Fondation Maladies RaresAlbinismImplementation of a next-generation sequencing analysis of a panel of genes involved in incomplete forms of albinism. -GIRCI SOHO 2019
2019David TOUBOULBordeauxGIRCI SOHO / Fondation Maladies RaresKeratoconus, EctasiaKeratoCone Eye Rub Questionnaire -GIRCI SOHO 2019
2019Maella SEVERINO-FREIEREToulouse GIRCI SOHO / Fondation Maladies RaresCutaneous mastocytosis Hydroxychloroquine in isolated cutaneous or indolent systemic mastocytosis with associated skin involvement: proof-of-concept study -GIRCI SOHO 2019
2019Gauthier RATHATMontpellierGIRCI SOHO / Fondation Maladies RaresCervical cancerValidation of the tool for detecting circulating tumor cells released during
cervical cancer surgery.
2019Pascale BOMONTMontpellierFoundation For Rare DiseasesGiant axonal neuropathyHit to Lead discovery for Giant Axonal Neuropathy -Hit to lead 2019
2019Yvon TROTTIERStrasbourgFoundation For Rare DiseasesHuntington's diseaseHit-to-lead development of amyloid aggregation modulators in Huntington's disease and pioneering a new synergic strategy to potentiate their use in therapy -Hit to lead 2019
2019Grégoire MICHAUXRennesFoundation For Rare DiseasesMicrovillus Inclusion Disease
Familial hemophagocytic lymphohistiocytosis type 5
Role of V0-ATPase in intestinal absorption and Microvillus Inclusion DiseaseCongenital diseases of intestinal absorption can lead to diarrhea that affects the survival of newborn infants. Microvillous inclusion disease is one such condition that can only be treated by total parenteral nutrition or intestinal transplantation. To better understand the origins of this pathology, we propose to create a new model using the nematode C. elegans, whose genome is easily modifiable and whose transparency allows direct, non-invasive observation of the intestine. By combining CRISPR/Cas9 genome editing and super-resolution microscopy,
we will develop an animal model that will initially enable us to better monitor the onset of the disease. Ultimately, we aim to use this model for high-throughput screening of small molecule libraries to identify potential new therapeutic approaches.
Models 2019
2019Thierry BIENVENUParisFoundation For Rare DiseasesAnorexia nervosaDevelopment of a new mouse model of anorexia nervosa, a knock-in mice model carrying a missense variant in the cholecystokinin A receptor (CCKAR)Anorexia nervosa (AN) is a complex psychiatric illness whose etiology remains uncertain. Recently, an association study identified the cholecystokinin type A receptor (CCKAR), expressed in peripheral tissues and the brain. Exome analysis in a familial form of AN has identified a new variant co-segregating with AN. This p.Cys387Tyr variant is located in the C-terminal cytoplasmic region of CCKAR in the S-palmitoylation site, involved in receptor internalization. Our project consists in introducing this variant into the corresponding position of the mouse CCKAR protein in order to reproduce a human model of AN. The study will investigate the consequences of the mutation on measures of peripheral and central metabolic components associated with reward abnormalities and on behavior, and test therapeutic strategies using CCKAR antagonists.Models 2019
2019Marc BAUD'HUINNantesFoundation For Rare DiseasesSpondyloepimetaphyseal dysplasia SEMDRIBOboneRibosomes are the cell's protein "factories", and their biogenesis and function are highly regulated. Certain disorders of these "factories", most of which are genetic in origin, lead to pathologies known as ribosomopathies. Our team has identified a new form of ribosomopathy
ribosomopathy responsible for a rare bone development disease: spondyloepimetaphyseal dysplasia. It is caused by mutation of a protein in the large subunit of the ribosome. Affected patients suffer from short stature, limb deformity and spinal deformity.
The generation of a mouse model will reveal the pathophysiological mechanisms and better characterize the events leading to this rare disease.
The RIBObone project will provide further insights into the production by ribosomes of essential factors for bone growth, and is part of a growing body of innovative research in this field.
Models 2019
2019Fabrice ANTIGNYLe Plessis RobinsonFoundation For Rare DiseasesPULMONARY ARTERIAL HYPERTENSIONRole of Orai1 in the pathogenesis of pulmonary arterial hypertensionPulmonary arterial hypertension (PAH) is a devastating disease characterized by increased pulmonary artery (PA) blood pressure, ultimately leading to right ventricular failure. It involves functional abnormalities of PA smooth muscle and endothelial cells, as well as cardiac cells. Our preliminary results indicate that Orai1 calcium channels contribute to pulmonary artery smooth muscle cell dysfunction. We aim to generate a rat strain
smooth muscle cells unable to produce a functional Orai1 protein. This animal model will enable us to study precisely the role of Orai1 in the pulmonary circulation, and provide evidence for the involvement of this Orai1 channel in the development of PAH. Ultimately, we aim to identify new therapeutic targets in PAH.
Models 2019
2019Massimo MANTEGAZZANiceFoundation For Rare DiseasesAutism, Intellectual Disability, Epileptic Encephalopathies, Neurodevelopmental DisordersKnock-in mouse model for studying and treating negative dominant SCN2A mutations: a novel pathological mechanism specific of autism mutants. The SCN2A gene codes for Nav1.2 sodium channels, which are essential for neuronal excitability. Mutations in this gene are responsible for neurodevelopmental diseases such as autism. The genotype-phenotype relationships and pathological mechanisms have yet to be elucidated.
Our preliminary in vitro results show for the first time that the SCN2A mutations responsible for autism induce a negative dominance effect that is not observed in any other disease. We have identified the region of the channel involved in this mechanism and are developing strategies to counteract the effect of the mutations.
We propose to develop a mouse model carrying an SCN2A autistic mutation, with the aim of validating our study in an integrated system to reveal a pathological mechanism specific to autistic mutations, and to test in vivo therapeutic approaches currently under development in vitro.
Models 2019
2019Daniel ABERDAMParisFoundation For Rare DiseasesANIRIDIA; EYE DISEASEProduction of iPSCs derived from patients with aniridia, a rare ocular disease caused by nonsense mutations in the PAX6 gene.Aniridia is a rare eye disease in which one of the most disabling symptoms is progressive corneal opacification (PCO). There is currently no treatment available. We have modeled ARK on limbal stem cells and identified by high-throughput screening two molecules already used in medicine for severe depression that restore the activity of mutated PAX6.
The aim of our project is to validate these two potential drugs for their eventual repositioning. To this end, we aim to derive induced pluripotent stem cells from the blood of 3 KRG patients. This will enable us to validate both molecules in the genomic/epigenetic context of the patients to be treated. As the cornea is easy to target with a topical formulation, the validation of these two molecules should enable the rapid development of a drug applicable in eye drops for the treatment of aniridia.
Models 2019
2019Christelle PEYRONLyonFoundation For Rare DiseasesNarcolepsy type 1Development of an hypocretin-KO rat model of narcolepsy type 1Narcolepsy type 1 (NT1) is a highly disabling orphan disease that affects 0.025-0.05% of the population and is characterized by daytime hypersomnolence and cataplexy, often associated with hallucinations, sleep paralysis and disturbed night-time sleep. NT1 is a chronic disease that generally appears in adolescence. We have shown that NT1 is due to the death of hypocretin neurons in the hypothalamus.
Cataplexy is a major symptom of narcolepsy. It is a loss of muscle tone during wakefulness (causing the patient to fall) which is induced by a positive emotion such as laughter or surprise.
There is no cure for this disease, current treatments are only symptomatic and the underlying neurobiological mechanisms are poorly understood. To better understand the activation dynamics between the neuronal populations involved, we will develop an original animal model of narcolepsy.
Models 2019
2019Laurence LEGEAI-MALLETParisFoundation For Rare DiseasesX linked hypophosphatemia
rare bone diseases
Zebrafish model of X-linked hypophosphatemiaMutations in the PHEX gene (phosphate regulating gene with homologies to endopeptidases on the X chromosome) are responsible for X-linked hypophosphatemia, resulting in abnormalities of the appendicular and craniofacial skeleton. The role of PHEX in craniofacial ossification is currently poorly understood. The establishment of a zebrafish line expressing a loss-of-function
loss-of-function mutation will provide a better understanding of the skeletal abnormalities induced by this mutation. The zebrafish is a model of choice for the study of craniofacial skeletal development, due to its many homologies with mammals. This model will also enable us to identify new therapeutic approaches, the zebrafish being an excellent model for screening molecules. Current treatments are very restrictive and do not allow us to treat all symptoms.
Models 2019
2019Frederic RELAIXCreteilFoundation For Rare DiseasesDuchenne Muscular DystrophyAccurate preclinical modeling and treatment proof-of-principle for Duchenne Muscular DystrophyDuchenne muscular dystrophy (DMD) is a rare neuromuscular pathology that mainly affects boys, resulting in the loss of dystrophin. Patients present with progressive muscle weakness, lose the ability to walk by the age of 10-12 and die of cardiorespiratory failure in the second or third decade of life. Persistent failures to transfer preclinical research in mice to humans demonstrate the need for laboratory animal models that faithfully mimic the disease state in humans. The preclinical models of Duchenne muscular dystrophy we aim to develop correspond to frequent human mutations and will enable us to design personalized genome-editing strategies integrated with our ambitious ongoing research program on preclinical therapeutic development.Models 2019
2019Thomas BOULINLyonFoundation For Rare DiseasesMutations in Neurobeachin have only very recently been identified as causing a spectrum of neurodevelopmental deficits (autism, neurodevelopmental disorders, ataxia, epilepsy, dysarthria). It is not yet identified as a specific disease.Modeling disease-causing mutations of Neurobeachin/NBEA in the nematode Caenorhabditis elegansNeurobeachin/NBEA is a brain protein involved in vesicular trafficking and the function and structure of synapses. Mutations in NBEA cause neurological disorders (autism, epilepsy, ataxia, dysarthria, neurodevelopmental disorders). The majority of mutations identified to date invalidate NBEA. However, direction-changing mutations whose impact is impossible to predict are also known.
are also known. However, to date, there is no model system in which this type of mutation can be rapidly characterized. Confirmation of the pathogenic effect of such a variant is a key step in the "diagnostic odyssey" of rare disease patients. The aim of this project is therefore to use the powerful genetic tools available in the nematode C. elegans (e.g. genome editing by CRISPR/Cas9) to study the effect of genetic variants of Neurobeachin, and to understand the molecular and cellular processes affected by these mutations.
Models 2019
2019Hamid-Reza REZVANIBordeauxFoundation For Rare DiseasesXeroderma pigmentosum type C (XP-C)Modelling of Pigmentary abnormalities in xeroderma pigmentosum type CRare diseases such as those linked to abnormalities in nucleotide excision repair (NER) are useful models for understanding complex diseases and developing new therapeutic strategies. The absence or dysfunction of the NER system leads to diseases such as xeroderma pigmentosum (XP). XP type C (XPC) is one of the most common forms in Europe, the USA and Japan. Homozygous individuals have a severe, early-onset sensitivity to the sun, which damages the skin and eyes. The term XP refers to the phenotype which includes the two clinical signs: xerosis and hyperpigmentation. However, hyperpigmentation in XP patients has been neglected until now due to the lack of a relevant model. We propose to investigate the role of XPC in pigmentation using the Xenopus model, which offers a unique opportunity to study melanocyte homeostasis.Models 2019
2019Nadia BAHI-BUISSONParisFoundation For Rare DiseasesSpinal Muscular Atrophy with Lower Limb predominance
Motor Neuron diseases
Investigating the cellular basis of DYNC1H1 related malformations of cortical development and spinal muscular Atrophy with lower limb predominance using targeted differentiation of human iPS cellsThe formation of neuronal circuits depends in part on axonal transport, which ensures essential communication between the tip and the cell body. In humans, dynein is a major player in this transport. DYNC1H1 mutations encoding dynein are responsible for a spectrum of diseases ranging from cerebral malformations (MCD) to a form of spinal muscular atrophy predominating in the lower limbs (SMALED). This diversity of disease expression would be linked to the variable consequences of mutations on dynein functions. We propose to study the impact of DYNC1H1 mutations in the principal clinical forms (MCD and SMALED; fetal and minor forms) of
the disease using patient fibroblasts harvested for IPSC formation. Our approaches will enable us to study the impact of mutations on the development of neural progenitors, motor neurons and on the development of cerebral organoids generated in our team.
Models 2019
2019Valérie DUPERennesFoundation For Rare DiseasesHoloprosencephalyASSESSMENT OF FUNCTIONAL RELEVANCE OF SYNONYMOUS VARIANTS IN SHH IDENTIFIED IN PATIENTS WITH HOLOPROSENCEPHALYHoloprosencephaly is a genetic developmental disorder characterized by cerebral and craniofacial anomalies of varying severity, the most severe form of which is cyclopia. In milder cases, the disease manifests itself as a single median incisor, close-set eyes and cleft lip and palate.
The genetic causes are still poorly understood; our latest results strongly suggest that mutations known as synonyms, which have long been ignored in medicine, are involved in the development of this pathology.
To test the relevance of our results, we need to determine the impact of these mutations on the development of a mammalian model, in this case the mouse.
This is why we are asking the Rare Disease Foundation for the financial resources needed to generate this unique model.
Models 2019
2019Olivier GOUREAUParisFoundation For Rare DiseasesInherited retinal dystrophies (Retinitis Pigmentosa)Modeling retinitis pigmentosa using retinal organoids derived from patient-specific induced pluripotent stem cellsRecent technological innovations have made it possible to manufacture pseudo-organs, or "organoids", from human cells transformed into stem cells (iPS cells). These in vitro models can be used to reproduce and study the cellular and molecular processes leading to specifically human diseases such as neurodegenerative diseases, particularly those affecting the retina. Our project consists in making 3D mini-retinas from cells of patients suffering from retinitis pigmentosa due to mutations in the Rhodopsin gene, to understand the development of this form of degeneration. These human iPS cell models are of major interest for understanding human diseases and designing new therapeutic strategies.Models 2019
2019Philippe LORYMontpellierFoundation For Rare DiseasesChildhood Cerebellar Atrophy (ChCA)A mouse model of Childhood Cerebellar Atrophy (ChCA) is required to decipher the pathogenic mechanism and to design a therapeutic optionOur team studies neurological diseases such as epilepsy and ataxia linked to ion channel mutations. We have just characterized new mutations in the gene coding for the Cav3.1 calcium channel, which are responsible for an extremely deleterious neurodevelopmental disease (infantile cerebellar atrophy, ChCA). These mutations are inherited in a dominant de novo fashion, are "gain of function" and most likely lead to massive neuronal death explaining the cerebellar atrophy. We aim to develop an animal model of ChCA to study the mechanism of the pathology, and to determine whether selective Cav3.1 channel blockers are capable of preventing or even treating the cerebral abnormalities caused by the Cav3.1 mutation. We have chosen to develop a mouse model, the most widely used preclinical model for which we have solid experience in exploring functions, including those of the cerebellum.Models 2019
2019Nathalie ANGEARDParisCNSAMyotonic dystrophy type 1 (DM1)Theory of Mind Training in Virtual Reality in the infantile form of Myotonic Dystrophy Type 1 (DM1)The infantile form of Myotonic Dystrophy type 1 (DM1) is a rare disease, little-known by doctors and even by the families concerned, as its presentation differs markedly from the congenital form (in its severity) and from the adult form. Affected children show few muscular signs, yet frequently have learning and social difficulties. These difficulties may stem from a disturbance in their Theory of Mind (ToM) skills, notably in their ability to recognize emotions and understand the intentions, desires or beliefs of others (mental states). Given this observation, it seems crucial to create a Virtual Reality (VR) training protocol focusing on emotional processing and theory of mind, and to offer it to children with DM1. The interest of this innovative environment lies not only in its ecological and attractive character, but also in the possibility of adjusting the complexity of social interactions between the different avatars according to the specific difficulties encountered by the participant.
The program will be offered to 35 children/adolescents with DM1 aged between 5 and 16. 6 training sessions will be held in environments reproducing familiar contexts such as a classroom, a playground or a camping camp. Participants will be able to virtually navigate through the environment, exploring settings, faces and understanding the mental states of different characters (e.g., saying the wrong thing and understanding the emotional impact on others) thanks to explanations provided by the experimenter. Ultimately, we expect to see an improvement in the ability to recognize and understand emotions. These pioneering results should eventually enable the creation of a serious game on a tablet that can be used at home.
Humanities and social sciences 7
2019Alexandra FOUBERT-SAMIERBordeauxCNSAMulti System AtrophyQuality of life for patients with multisystem atrophy and their caregiversMultisystem atrophy (MSA) is a rare, progressive neurological disease caused by the loss of neurons (atrophy) in several brain regions (several systems=multisystem). Occurring between the ages of 50 and 70, it is characterized by a combination of motor disorders causing gait problems associated with genito-urinary disorders, malaise due to a fall in blood pressure (orthostatic hypotension), and speech and swallowing disorders. To date, this pathology is incurable, and its very severe prognosis leads to significant disability in 4 to 5 years, with an average lifespan of 8 to 9 years. As with other neurodegenerative diseases, the absence of curative treatment and the rapid progression of AMS patients mean that the family and especially the caregiver are at the heart of their care. The quality of life of both patient and carer is rapidly affected. In this context, the rare disease reference center
for AMS wishes to assess whether targeted medico-psycho-social support tailored to the concerns of the patient and caregiver could improve the couple's emotional and social quality of life. To this end, we will adapt a program developed by Prof. Mittelman, the New York University Caregiver Intervention (NYUCI), which is recognized for its support of caregivers and their families in other pathologies. This program consists in identifying the needs of the patient-caregiver couple, with a view to improving day-to-day management by involving those around them. A total of 72 couples will be included, half of whom will receive the intervention immediately and the other half with a 6-month delay. We will evaluate whether, at 6 months, the quality of life of the intervention group has improved. The ARAMISE association will accompany us in this program, and will be able to provide support to families as a relay to the intervention.
Humanities and social sciences 7
2019Amélie ROCHET-CAPELLANGrenobleCNSAAngelman syndromeParticipAACtion: A participatory corpus of Augmentative and Alternative Communication for people with rare neurogenetic syndromes to understand and improve itCertain rare genetic diseases affect the functioning of the brain as a whole, altering the person's perceptual-motor and intellectual capacities to varying degrees. These multiple difficulties mean that speech is often impossible or severely restricted, as in the case of Angelman syndrome (AS). Yet caregivers' testimonies and research into Augmentative and Alternative Communication (AAC, i.e. means of communication other than speech such as manual gestures, images, tablet software, etc.) show that these people have communicative skills and needs like everyone else. Some caregivers use AAC to support their loved one's or patient's communication, while a majority of others are unable to express themselves to the extent of their skills, or to develop their communicative potential. This is partly due to the fact that very little research has been carried out into the communication of people with this type of disorder, and that conventional methods of communication research are not adapted to these people. In order to overcome these limitations, the ParticipAACtion project proposes a participatory and interdisciplinary approach consisting in creating and analyzing an audio-visual corpus of the communication of people affected, filmed in their daily lives by their relatives. The project involves researchers in language and communication sciences, a French association of families with Angelman syndrome, the DéfiScience rare disease health network and the Handéo association, as well as caregivers who will take part in collecting and analyzing the recordings and interpreting the results. The results should make it possible to identify the tools and contexts that promote communication, enhance the skills of the people concerned, and contribute to the development of the use of AAC.Humanities and social sciences 7
2019Jean-Pierre POULAINToulouseCNSA / Fondation Maladies RaresPrader-Willi syndromeSocialization of the Feeding Practices of Children with Prader-Willi Syndrome - SoPAPPrader-Willi syndrome (PWS) is a complex neurodevelopmental disorder linked to a gene expression defect. People with PWS present somatic, cognitive and behavioral disorders. Throughout development, the disease is characterized by "severe eating disorders" with consequences for the child's health and social life, as well as for the family environment. In this pathology, the biological and psychological dimensions of eating are described, while the socio-cultural dimensions are only mentioned. What's more, our knowledge of eating behaviours is mainly based on what people with PWS and their parents have to say, or on observations made in care settings.
Using an interdisciplinary approach, this research aims to understand the (de)socialization of children with PWS into ordinary life by describing and analyzing the construction of eating practices and parental management of these practices, which are described as problematic.
Survey data will be collected using 3 methodological devices: individual interviews, observations of family meals (at home and in experimental situations) and telephone questionnaires with a larger number of families. Analysis of the data will enable us to simultaneously construct a typology of food neophobia, describing and explaining the individual, family, health and social issues facing this population. Finally, this work aims to update and develop concrete applications (information and support tools) co-constructed "by" and "for" the family, associative and professional players present on a daily basis, and could serve as a reference for other pathologies with neurodevelopmental disorders.
Humanities and social sciences 7
2019Marcela GARGIULOParisCNSASpinal Muscular AtrophyProject: PARENTALITY and Spinal Muscular Atrophy. Multidimensional study of parental overload Franco-Chilean studySMA is the 2nd rare disease of genetic origin (approximately 1/10,000 births). It is characterized by progressive muscular atrophy leading to disability. Parenting a sick child with a severe disability is an ordeal that can disrupt the experience of parenthood. The involvement of parents in daily long-term care, the medicalization of the relationship and their participation in sometimes dilemmatic therapeutic decisions can modify the exercise, practice and experience of parenthood. Objective: to study the specificity of representations of parenthood, to evaluate and analyze the feeling of parental overload, including the search for risk and protective factors. Partners: this is an interdisciplinary collaboration, with 3 neuropediatric consultations
(Trousseau, I-Motion and Raymond Poincaré hospitals) and the AFM's regional services. Population: 60 parents of children with SMA (types 1, 2 and 3), recruited through the 3 consultations. Methodology: mixed methodology, using qualitative and quantitative tools. Innovative aspects: first study carried out in France. The expected results could have a high degree of transferability to other serious genetic diseases of children. The mixed methodology will enable us to identify parental representations and the determinants of parental overload, with a view to developing intervention programs. Comparison of our results with those of the Chilean team will enable us to determine whether the health and inclusion policies of the two countries are determinants of parental overload.
Humanities and social sciences 7
2019Pascal ANTOINELilleMGEFI / Fondation Maladies RaresHuntington's disease, Huntington's choreaDyade: Couple dynamics in Huntington's diseaseTaking into account and integrating the patient's family and friends is a major factor in improving the quality of patient care. A growing number of studies are focusing on the experiences of caregivers confronted with Huntington's disease, demonstrating the importance of considering the physical and emotional impact on those around them, and the support they can receive. Huntington's disease is a rare genetic disorder that affects young people, with serious consequences for those around them, especially couples. The issues specific to the different stages of the disease are likely to call into question the balance of this affective system and its protective role for each individual. Studies have highlighted the difficulties faced by each partner in isolation. Research is needed, however, to understand the difficulties of both partners, their experiences as a function of the stage of the disease, how both partners adjust (or fail to adjust) to symptoms and care, and to each other. Overall, dyadic functioning is poorly documented. As a result, as yet underdeveloped support systems are unable to integrate this essential dimension of quality of life and care. Our aim, therefore, is to understand the functioning of couples confronted with illness, in order to identify the processes that deteriorate the quality of life of both spouses and those that contribute to their resilience. Thirty couples and fifteen spouses-caregivers will be asked to talk about their experiences. These interviews will be recorded, transcribed and qualitatively analyzed to identify dyadic processes and understand the evolution of interactions during the illness. The results will serve as a clinical basis for identifying and supporting people in difficulty.Humanities and social sciences 7
2019Agnès DUMASParisFE IRCEMSystemic lupus erythematosus, Juvenile idiopathic arthritisTransition of care and well-being for young adults with juvenile idiopathic arthritis and systemic lupus erythematosus (Transcare)Adolescence and early adulthood represent an important period for young people suffering from rare systemic inflammatory rheumatic and autoimmune diseases (RAISE): they must prepare to assume responsibility for their health independently and cope with the consequences of the disease and its treatment, while also facing the psychological and social challenges typical of adolescence.
The few existing studies on the fate of RAISE patients following the transition
transition show that a significant proportion are lost to follow-up or experience increased disease activity. Ultimately, little is known about the factors that promote transition in these young people.
The main aim of our research is to quantify and understand the individual and organizational factors influencing the successful transition of care for these young patients, and to identify the psychosocial difficulties associated with this period.
In addition, we wish to integrate the point of view of young patients, their caregivers and professionals.
The research will use mixed methods (questionnaires and interviews).
The quantitative component will focus on 120 young people aged 18 to 23, referred to adult services, with juvenile idiopathic arthritis or systemic lupus, followed up in the participating centers. A component of the study will also involve the parents of these young people. Several variables relating to the outcome of the transition will be quantitatively measured, both subjectively (notably the establishment of a relationship of trust with the adult physician) and objectively (through medical record data), and individual (clinical and social) and organizational (practices around the transition) factors will be analyzed. Several questionnaires will be used to collect data from young people, their parents and clinicians.
Humanities and social sciences 7
2019Naziha KHEN-DUNLOPParisAssociation (APEDHia)Developmental anomalies and malformation syndromesFETAL LUNG EVALUATION ON BOLD-MRI IN CONGENITAL DIAPHRAGMATIC HERNIA -Spouse with association
2019Bertrand DIEUSAERTHirsonAssociatif (AFAF) / IRCEM Corporate FoundationRare neurological diseases COM-ATAXIE Research of innovative solutions to help communication for ataxic people (Friedreich's ataxia and close ataxias) via digital tools -Spouse with association
2019Guillaume CANAUDParisIRCEM Corporate FoundationHypergrowth syndromesHypergrowth syndromes: improving patient outcomes -Outside AAP
2020Trang HAParisFoundation For Rare DiseasesCongenital Central Hypoventilation SyndromeCongenital Central Hypoventilation Syndrome - searching causal genes in patients without PHOX2B mutations -GenOmics 2019
2020Julien BARCNantesFoundation For Rare DiseasesNew rare cardiac syndrome associated with an enhancer deletion of chromosome 4q25Molecular mechanism of a new syndrome characterized by cardiac electrical and developmental defects and associated with an enhancer deletion of chromosome 4q25 -GenOmics 2019
2020Julie STEFFANNParisFoundation For Rare DiseasesMitochondrial diseasesDoes nuclear transfer alter mitochondrial-nuclear crosstalks in the human preimplantation embryo? -GenOmics 2019
2020Benoit ARVEILERBordeauxFoundation For Rare DiseasesAlbinismSearch for new albinism genes -GenOmics 2019
2020Pierre-Louis THARAUXParisFoundation For Rare DiseasesGlomerular Diseases"TRAJHISTORY project: assessing single cell TRAJectories and alterations of cell communication and tissue HISTOry to get causal insights into rare and catastrophic glomerular diseases" -GenOmics 2019
2020Pierre RONCOParisFoundation For Rare DiseasesPLA2R-Associated Membranous NephropathyWhole Genome Sequencing to Unravel the Genetic Mechanisms
of PLA2R-Associated Membranous Nephropathy
-GenOmics 2019
2020Caroline SCHLUTH-BOLARDLyonFoundation For Rare DiseasesNeurodevelopmental DisordersCharacterization of 3D chromatin architecture disruption in chromosomal rearrangements to identify candidate genes in neurodevelopmental disorders -GenOmics 2019
2020François-Xavier MAUVAISParisFoundation For Rare DiseasesLysosomal Acid Lipase (LAL) deficiencyIdentifying the molecular basis underlying the heterogeneity among the spectrum of lysosomal acid lipase deficiency by a proteogenomic approach supported by bioinformatics -GenOmics 2019
2020Alexandre FABREMarseilleFoundation For Rare DiseasesCongenital Diarrhea SyndromeIdentification of new genes associated with syndromic congenital diarrhea syndrome -GenOmics 2019
2020Marion DELOUSLyonFoundation For Rare DiseasesIdiopathic scoliosis (IS)Towards the identification of the genetic causes of rare autosomal dominant forms of idiopathic scoliosis -GenOmics 2019
2020Sylvie MAZOYERLyonFoundation For Rare DiseasesRNU4ATAC-associated rare diseasesA transcriptomic study in zebrafish models of RNU4ATAC-associated rare diseases: connecting U12 splicing defects to developmental abnormalities -GenOmics 2019
2020Laura MARYRennesFoundation For Rare DiseasesDisorders of sex development (DSD)Identification of genes involved in syndromic disorders of sex development -GenOmics 2019
2020Valerie DESQUIRET-DUMASAngersBPGO FoundationMitochondrial pathologiesTherapeutic potential of Niclosamide in mitochondrial pathologies (PRINCIPLE) -Outside AAP
2020Sophie NICOLEMontpellierFoundation For Rare DiseasesMonogenic motor channelopathies Search for isoform-selective sodium channel modulators to treat monogenic motor channelopathies Ion channels are proteins which, as their name suggests, transport ions passively and more or less selectively across biological membranes. These proteins play a central role in physiology, being involved in the electrical activity - a process defined as excitability - of a large number of cell types, including neurons, muscle cells and endocrine cells. Considering their central role in major physiological functions such as locomotion, nociception and respiration, mutations in ion channels altering their function induce sometimes severe or even lethal human pathologies, known as channelopathies.
In Montpellier, the "Ion channels in neuronal excitability and channelopathies" research team is focusing here on two members of the sodium channel family whose genetic mutations generate rare motor pathologies: the voltage-sensitive sodium channel Nav1.4, expressed exclusively in skeletal muscle, and the leaky sodium channel NALCN, expressed in numerous neurons and endocrine cells. Only expressed in skeletal muscle, loss-of-function mutations in Nav1.4 are responsible for neuromuscular diseases characterized by muscle weakness of varying severity (from lethal at birth in the most severe forms, to transient muscle weakness in response to certain factors in the least severe forms). With a broader tissue expression, loss-of-function or gain-of-function mutations in NALCN are at the origin of clinically complex neurodevelopmental syndromes (CLIFAHDD, IHPRF1) of varying severity, associating several neurological symptoms: hypotonia, facial dysmorphism, global developmental delay and others.
Today, there are no drugs that can improve the symptoms of patients suffering from these rare genetic diseases. However, many molecules, both natural and chemical, are capable of modulating ion channel function. The ambition of our project is therefore to identify compounds that modulate Nav1.4 or NALCN activity, by screening libraries of chemical compounds (CNRS chemical compound bank) or natural compounds (spider toxins) using an automated electrophysiological recording screening method (known as "patch clamp") developed by the Therassay platform (Nantes). In particular, we hope to identify Nav1.4 activators and NALCN inhibitors that can then be tested in preclinical models (zebrafish) of these diseases, which the Montpellier team is currently characterizing.
High throughput screening / Hit to lead 2020
2020Lucile HOCHEvryFoundation For Rare DiseasesGlycogen Storage Disease Type IIIUse of pluripotent stem cells to model and treat GSDIIIGlycogen storage disease type III (GSDIII) is a rare genetic disorder (prevalence approx. 1 in 100,000 births) caused by an enzyme deficiency leading to abnormal accumulation of glycogen in the liver and muscles, preventing them from functioning properly. To date, the only treatments available are symptomatic and rely on strict diets to regulate liver abnormalities, but no treatment to improve muscle weakness is currently available. Gene therapy studies have been developed with the aim of replacing the defective gene and treating the disease. However, these therapies are currently unable to simultaneously treat the liver and muscle defects caused by this pathology. The aim of our program is to use pluripotency-induced stem cells (iPSCs) carrying the disease, capable of infinite self-renewal and differentiation into any cell type, to model the muscular damage caused by GSDIII. This study will enable us to gain a better understanding of the molecular mechanisms underlying these pathological defects, as well as to carry out high-throughput screening studies of potentially therapeutic compounds.High throughput screening / Hit to lead 2020
2020Veronique STOVENParisFoundation For Rare DiseasesCystic FibrosisNew drugs for Cystic Fibrosis based on machine-learning approachesCystic fibrosis is caused by mutations in a gene coding for the CFTR protein, whose known function is to transport Cl- ions. In cystic fibrosis, CFTR is absent or no longer performs this function. Drugs to restore its presence and function (known as "CFTR modulators") have become available in recent years, but the precise mechanism of action of these drugs has not yet been established, which is an obstacle to optimizing these treatments. Identifying the mechanism of action of these molecules is an important issue for improving therapies.
Our project aims to use artificial intelligence algorithms developed in our team to identify these mechanisms of action, and to validate them experimentally. Knowledge of these mechanisms will enable us to suggest new therapeutic strategies and new drugs to be tested experimentally on respiratory cells from cystic fibrosis patients. We will give priority to opportunities for repositioning known drugs in cystic fibrosis, in order to limit the time required for clinical development.
High throughput screening / Hit to lead 2020
2020Eric DURANDMarseilleFoundation For Rare DiseasesCystic FibrosisTowards the development of Pseudomonas aeruginosa "virulence blockers" targeting the T6SS nanomachine: A Hits-To-Lead approachThe prognosis of cystic fibrosis is primarily influenced by the pulmonary course of the disease, and especially by chronic bacterial colonization. Pseudomonas aeruginosa, a Gram-negative bacterium, is the most common opportunistic pathogen in cystic fibrosis patients. Primary infection with Pseudomonas aeruginosa in these patients is a crucial stage in the development of the disease and its pulmonary consequences. Infection precipitates lung decline, and may become permanent if not rapidly eradicated. Antibiotic treatment to combat Pseudomonas aeruginosa in patients is increasingly ineffective due to the emergence of multi-resistant strains. There are many different detection methods and treatment regimens available, and there is currently no consensus as to the best course of treatment. We therefore need to develop new therapeutic solutions, such as blocking the development of Pseudomonas aeruginosa virulence at an early stage.
The aim of our project is to develop a new therapeutic approach targeting the virulence of Pseudomonas aeruginosa, in particular by blocking the first essential stages in the colonization of patients' lungs. Pseudomonas aeruginosa uses an arsenal of "small molecular weapons" that enable it to colonize humans and develop its pathogenic power. One of these weapons, the "T6SS", enables the "firing" of powerful toxins which, on the one hand, enable Pseudomonas aeruginosa to kill "beneficial" bacteria and thus colonize its site of infection, and, on the other, to enter human lung cells to hide from the immune system, contributing to the chronicity of the infection. The aim of our project is to explore the concept of blocking a virulence factor as a new anti-pyo therapeutic approach. The consortium is expert in the fundamental knowledge of the targeted virulence factor and has already set up a pipeline to identify inhibitors. The project will enable the development of future drug candidates that should limit the virulence of "pyo".
The main cause of mortality in cystic fibrosis patients is infection of the lungs by different bacteria, which vary with age. The bacterial composition in patients' lungs is modulated by intense competition between different species vying for resources and space. Pseudomonas aeruginosa appears progressively over the course of a patient's life, and dominates at the end of life. This pathogen possesses a "weapon", the T6SS, which enables it to reign hegemoniously over other bacterial populations, and also to interact with patients' lung tissue. Bacterial infections are usually treated with antibiotics. However, Pseudomonas aeruginosa is becoming multi-resistant to antibiotics, making treatment very difficult and making pulmonary bacterial infections the major cause of mortality in cystic fibrosis patients. Our research project aims to improve the management of bacterial infections in the future by developing new means of combating "pyo", such as anti-T6SS molecules.
High throughput screening / Hit to lead 2020
2020Sandrine GULBERTINancyFoundation For Rare DiseasesMucopolysaccharidosesDevelopment of a specific inhibitor of the glycosyltransferase β4GalT7 for substrate reduction therapy in mucopolysaccharidoses: towards the hit to lead stageMucopolysaccharidoses (MPS) are rare genetic diseases caused by a defect in the degradation of mucopolysaccharides, large carbohydrate molecules present in the body's tissues. As they are not degraded, they accumulate in cells, producing multiple severe organ damage, particularly in the brain, reducing patients' quality of life and lifespan. The aim of the project is to propose new molecules that could lead to more effective and less burdensome treatments, in particular by improving the neurological symptoms of the disease. We are seeking to develop a small molecule that specifically blocks a step in the synthesis of mucopolysaccharides in order to reduce their accumulation in tissues and their deleterious effects. To this end, we have chosen as our target one of the proteins involved in the early stages of the synthesis process. In the first stage of the project, we tested a large number of chemical compounds for their ability to block the mucopolysaccharide synthesis pathway, and selected the best inhibitor molecules. In this project, we propose to validate the choice of these molecules and, in a second phase, to optimize them to obtain even more effective molecules using complementary approaches combining medicinal chemistry and virtual models generated by software and computer programs developed for these purposes. We hope that this project will provide a new avenue of treatment in the context of mucopolysaccharidoses.High throughput screening / Hit to lead 2020
2020Thierry LEVEILLARDParisFoundation For Rare DiseasesRetinitis pigmentosaBlindTimee: Reconstruction of the cone-photoreceptor outer segment to recover vison in a large model of retinitis pigmentosa -Translational research 2019
2020Nathalie ANGEARDParisFoundation For Rare DiseasesCongenital central hypoventilation syndromeAttentional resources in children with Ondine syndromeOndine syndrome is a rare disorder characterized by severe alveolar hypoventilation (hypoxemia and hypercapnia) linked to an anomaly in the central autonomic control of breathing. The disease often reveals itself in the neonatal period, and management may involve lifelong ventilatory assistance. Children with Ondine syndrome nonetheless present significant learning difficulties, despite rehabilitative treatment. Although few studies have focused on cognitive disorders, recent data have highlighted deficits in the attentional sphere. These initial findings are in line with the everyday complaints reported by parents, and could explain the learning difficulties.
The aim of this multidisciplinary project is not only to assess the overall attentional capacities of children aged 6 to 16 with Ondine syndrome, but also to study the impact of spontaneous breathing on attentional processes (and vice versa) through a dual-task situation.
The study will involve 20 patients aged 6 to 16 with Ondine syndrome at Robert Debré Hospital, and 40 age- and sex-matched control subjects from schools in the Paris region. In the 1st phase, we will evaluate the sustained, divided and selective attention capacities of children with Ondine syndrome, in comparison with the control group. In a 2nd phase, we will place Ondine patients in a situation where they will have to manage their breathing alone or at the same time as performing an attention task. Highlighting the cognitive cost of breathing in dual-task situations in this rare disease will provide a better understanding of the limitations faced by these patients, whether in learning situations at school or in their social interactions.
Humanities and social sciences 8
2020Karinne GUENICHEParisFoundation For Rare DiseasesMayer-Rokitansky-Küster-Hauser syndromeEvolution of the psychosocial impact of the diagnostic announcement of Rokitansky syndrome: EIPSAMRKH5The announcement of an absence of uterus and vagina (MRKH syndrome), usually during adolescence, leads to intense psychological suffering linked to the difficulty of accessing sexual life and motherhood.
We recently carried out a large-scale study of the overall and sexual quality of life of 131 MRKH patients who completed validated self-questionnaires (WHOQOL-bref, FSFI, FSDS-R). Among them, 40 benefited from a more in-depth assessment of the psycho-social impact of the diagnosis, using a semi-structured interview and Rorschach and TAT projective tests to evaluate their psychic functioning at a given point in their history.
The results showed an alteration in sexual quality of life, with a genuine experience of disability, and unexpectedly, addictive eating disorders (anorexia/bulimia) or sports disorders, and an over-representation of heterosexual orientation compared with the general population. The absence of a uterus led to severe suffering. Projections of access to biological motherhood were essentially focused on GPA.
In the light of these data, derived from real encounters with patients, our aim is to assess the evolution of these results, by re-evaluating the psychic functioning of the same 40 young women using the same methods, more than 5 years after the first evaluation. We hope to find an improvement in overall and sexual quality of life, and a disappearance of addictive disorders at a distance from the diagnosis. The desire to have children is likely to be expressed more frequently and more painfully, given the advancing age of young women.
The identification of psychosocial prognostic factors should enable us to improve our already multidisciplinary care practices, particularly in the psychological field. This could also benefit other women with rare diseases affecting their sexuality and/or fertility.
Humanities and social sciences 8
2020Barbara LE DRIANTAmiensAG2R La MondialePermanent neonatal hearing impairmentAccompanying parents faced with the diagnosis of permanent neonatal deafness: analysis of difficulties and needs.Hearing is an essential function for communicating with others. It is not unusual for a newborn to present with a severe hearing anomaly (1 per 1000 births), even though the parents are hearing. Without early diagnosis, hearing loss exposes the child to a risk of delayed development of language, learning and social skills. The decree of April 23, 2012 has systematized the early identification of deafness in newborns, in order to intervene appropriately by ensuring the child's development is as harmonious. as possible. This medical benefit is only optimal if it is coupled with long-term support for parents, and this right from the maternity ward, as the diagnosis often leaves parents very worried and at a loss.
Objectives: The aim of this project is to study how each parent experiences the diagnostic process, from screening to caring for their child, and to identify the difficulties encountered and the essential resources for improving the quality of support.
Method: Parents with no family history of deafness will be included, whose child born between 2012 and 2017 presents a bilateral, moderate to profound deafness at birth, with no other associated disorder, and whose genetic origin is confirmed. Data collected through interviews and questionnaires will be analyzed both qualitatively and quantitatively.
Expected results and impact: A better understanding of parental experiences and needs will enable the development of optimized support programs, by raising awareness and training medical and social staff in existing strengths and limitations.
Relevance of the project: As children grow up within their families, it is essential to find ways of supporting them. It is essential to find ways of easing the delicate process of diagnosing deafness by developing and improving support for parents, based on their experiences, needs and expectations.
Humanities and social sciences 8
2020Yannick LE HENAFFRuenFoundation For Rare DiseasesCongenital diaphragmatic herniaEngagement in physical activity and sport in adolescents with diaphragmatic dome herniacHernia of the Diaphragmatic Cupola (HCD) is a rare congenital condition, most often diagnosed in the ante-natal period, characterized by incomplete or absent formation of the diaphragm during uterine life, enabling abdominal organs to ascend into the thorax.
According to several studies, the quality of life and physical capacities of these children, who undergo surgery from birth, appear to be correlated with their level of physical activity and sport, which is also lower in these individuals. Research conducted to date, while leading to this observation, has not investigated the reasons for the low rate of sporting activity among these children.
The aim of this research is therefore to assess the level of physical activity in children followed up by the Diaphragmatic Hernia Reference Center, and above all to understand the possible obstacles, when encouraged by the referring physician. After highlighting the obstacles and facilitators (and identifying the underlying mechanisms), a support program will be co-constructed with the APEHDia patient association to support parents and children at every stage of the treatment process.
Our hypothesis is that the relationship with physical activity, in addition to objective somatic reasons (cardiac and respiratory), is constructed in relation to CDH and the traumas it can generate, but also in relation to different forms of socialization, which help to define the relationship parents have with their children's bodies and physical activity. The diversity of the experiences of these children and their families is thus partly reflected in the complex combinations of inequalities and life trajectories that will be unravelled.
The methods used will be essentially qualitative, based on life-story interviews with 20 parents and 10 teenagers between the ages of 14 and 18.
Humanities and social sciences 8
2020Pierre LOMBRAILParisFoundation For Rare DiseasesCystic FibrosisPatient Experience of the Cystic Fibrosis Pathway during the Covid-19 pandemicThe Covid-19 crisis put healthcare systems to the test, and patients, particularly those with rare and chronic diseases such as cystic fibrosis, may have encountered specific management difficulties during this period. Recent information shows that patients and their families mobilized strongly during the crisis period to avoid infection by Covid-19, by implementing new strategies or reinforcing barrier measures already anchored in the lives of these patients.
The ExPaParM-Covid project is a collaborative research project involving patients and parents trained as "co-researchers", clinicians and researchers. It will provide an opportunity to interview patients and parents directly about their experience during the health crisis, in order to understand the specific needs that may have emerged for their care, health and life paths. Based on the analysis of this experience, discussions will be held with teams from specialized cystic fibrosis hospitals. This will also be an opportunity to gather the experience of caregivers during the crisis, identifying problematic or beneficial elements to be maintained outside the crisis period, or to be anticipated in the event of a future health crisis. Finally, this work on the cystic fibrosis community will enable us to engage in a dialogue with the networks and patient associations of other rare diseases, and to make an international comparison of crisis management. ExPaParM- Covid will thus provide an opportunity to cross-reference the experience of patients and caregivers during this exceptional period, with the aim of drawing up scenarios for management in times of health crisis, and identifying effective levers for the future.
Humanities and social sciences 8
2020Alain LOUTELilleFoundation For Rare DiseasesAmyotrophic lateral sclerosisEvaluation of the ethical and legal stakes of the use of telemedicine in the context of the accompaniment of patients with advanced Amyotrophic Lateral SclerosisDiseases on the Amyotrophic Lateral Sclerosis (ALS) spectrum, affecting almost 6,000 people in France, are rare neurodegenerative diseases (incidence 3/100,000) affecting central and peripheral motor neurons in adults, with incidence increasing from the age of 40 onwards. The advanced stage of the disease is a critical period, with a high risk of complex, inadequately controlled symptoms, and hospitalization that can be difficult to cope with. In this context, studies have shown that teleconsultation (TLC) can be useful. TLC is a remote consultation between the hospital doctor and the patient at home. It helps to improve the quality of care in the advanced stages of the disease, right up to death, by limiting hospital admissions, preventing complications and caregiver burnout, and providing access to palliative care.
This project continues the evaluation of TLC for advanced ALS patients, but focuses on the question of its ethical and legal impact, which has received little attention in the literature. TLC is not without effect on the patient's living space. Connecting the hospital doctor to the home has the effect of hybridizing the hospital space with that of the home. Conversely, the space of the home can disrupt TLC. Through semi-directive interviews with 40 patients, the project aims to assess the impact of TLC on patient intimacy. Alongside this research objective, the project will also assess the impact of TLC on the quality of the medical relationship. Communication media influence the way we communicate. Using interviews and a questionnaire for ALS Centers, the project will assess how the telemedicine system transforms this relationship. Thanks to this project, it will be possible to better identify the ethical and legal risks associated with the practice of TLC, and how to prevent them.
Humanities and social sciences 8
2020Alexandre MATHIEU-FRITZMarne-la-ValléeFoundation For Rare DiseasesCystic FibrosisSociological study of the support to autonomy in health of adult patients with cystic fibrosis with the help of new technologies and with liberal health professionalsThis research project is proposed as an extension of the project entitled "Accompagnement à l' autonomie en santé des patients adultes atteints de mucoviscidose à l'aide des nouvelles technologies et en partenariat avec leur équipe soignante" (AAST-MUCO) which has been selected by the Association Gregory Lemarchal, as part of its 2019 call for projects. The AAST-MUCO project involves setting up a sociological evaluation of the "Assistant de Vie Mucoviscidose" (AVM), a self-monitoring device that aggregates several life data made up of measurements taken via connected objects, as well as feelings and treatments entered manually by patients. The aim of this project is to study the use of MVA in order to assess its impact on patients' experience and participation in the management of their disease, as well as, more generally, on the organization of cystic fibrosis care in hospitals. The study is based on a longitudinal approach, involving several series of semi-structured interviews with members of the CRCM care team at the Foch Hospital in Suresnes, and a panel of 15 patients selected and followed up by them.
The present research project completes this sociological study with two main extensions. The first is to include all the other healthcare professionals involved in the organization of cystic fibrosis care, beyond the hospital setting. In fact, this extension to all the liberal professions (physiotherapists, nurses, pharmacists, psychologists and/or coaches, etc.), is essential if we are to grasp the effects of integrating the new self-monitoring tools into the overall organization of cystic fibrosis care. A second extension consists of integrating into this analysis the specific questions that emerge with the new context of care in the Covid-19 era.
Humanities and social sciences 8
2020Aurore PELISSIERDijonFoundation For Rare DiseasesIntellectual diasbility (ID)Helping Configurations and Employment Situations for Caregivers. The case of children with rare diseases and intellectual disabilities. A pilot study.cCASEPRA Pil is a pilot project designed to initiate research into the configurations of assistance organized around children with rare diseases and intellectual disabilities, and the repercussions of this assistance on the lives of parent carers. The first step is to identify who the caregivers are, and to characterize the nature and intensity of the assistance they provide. This "support network" will be compared with the professional care provided for the person being cared for. The aim is then to analyze the impact of assistance on the employment situation and working life of parent carers.
To meet these objectives, the pilot project aims to design the questionnaire survey to be administered to parents nationwide. The project is divided into two phases. The first, qualitative exploratory phase aims to define the subject more precisely. It is based on semi-directive interviews. The second phase, known as the operationalization phase, comprises two stages, with the aim of preparing the survey and developing the questionnaire.
CASEPRA Pil is a collaborative project bringing together a team of social science researchers from two disciplines (economics and sociology), two rare disease health networks, a handicaps rares relay team (Bourgogne Franche-Comté branch), UNAPEI and the eNorme network. The aim of the project is to fill a data gap in the field of caregiver analysis for children with disabilities, by producing a targeted survey that will enable the appropriate levers to be activated to meet the needs of family caregivers. Indeed, this research will help identify the specific support needed to best accompany informal caregivers, with the aim of improving their well-being and, ultimately, the care of the person being cared for.
Humanities and social sciences 8
2020Aloise MABONDZOSaclayAssociative (Xtra)Rare neurological diseases Development of a future drug to treat creatine transporter deficiency -Spouse with association
2020Pedro Henrique DE LIMA PRATAParisAssociative (HPN)Rare non-malignant hematological diseases Inherited complement regulatory gene mutations in paroxysmal nocturnal hemoglobinuria: an influence in disease presentation and treatment efficacy? -Spouse with association
2020Simona PAGLIUCAClevelandAssociative (HPN)Rare non-malignant hematological diseases Immunogenomics of idiopathic bone marrow failure disorders: immune-escape mediated by class I/II HLA somatic mutations -Spouse with association
2020Julien NIZARDNantesAssociative (Algo France)Rare neurological diseases Towards a better consideration of patients' feelings in complex regional pain syndrome (CRPS): a study mixing quantitative and qualitative approaches to test and make recommendations regarding the use of a Body Perception Disturbances (BPD) assessment tool. -Spouse with association
2020Valérie DESQUIRET-DUMASAngersGroupama Loire BretagneHereditary metabolic diseases Targeted-therapeutic approaches to restore oxidative metabolism in rare diseases associated with mitochondrial complex I mutations -Outside AAP
2020Marie-Paule GELLEReimsIRCEM Corporate FoundationRare head and neck malformationsImproving the care pathway for children with rare dental anomalies -Outside AAP
2020Isabelle TALONStrasbourgIRCEM Corporate FoundationDevelopmental anomalies and malformation syndromesImproving the Care and Life Course of Children with Congenital Diaphragmatic Hernia -Outside AAP
2020Véronique DANEL BRUNAUDLilleIRCEM Corporate FoundationNeuromuscular disordersImplementation of teleconsultations for patients affected by advanced Amyotrophic Lateral Sclerosis and treated in Hospitalisation à Domicile (HAD) -Outside AAP
2021Sara BALDASSARRIParisFoundation For Rare DiseasesFocal Cortical Dysplasia (FCD)Dissection of the genetic etiology of epilepsy with focal cortical dysplasia -GenOmics 2020
2021Guilaine BOURSIERMontpellierFoundation For Rare DiseasesAmyloidosis of unknown cause (AAx)Exome sequencing of inflammatory amyloidosis of unknown cause (AAx) -GenOmics 2020
2021Clément CARREParisFoundation For Rare DiseasesIntellectual diasbility (ID)Lost in translation: RNA methylation controls translation in ID patients mutated in FTSJ1 -GenOmics 2020
2021Svetlana GOROKHOVAMarseilleFoundation For Rare DiseasesEarly infantile epileptic encephalopathyIntegrating transposable element screening into the diagnostics of patients with rare genetic diseases -GenOmics 2020
2021Gilles LAVERNYIllkirchFoundation For Rare DiseasesIdiopathic Infantile Hypercalcemia (IIH)Identification of ZK therapeutic activities for Idiopathic Infantile Hypercalcemia -GenOmics 2020
2021Jean-Yves PICARDParisFoundation For Rare DiseasesPersistent Müllerian duct syndrome (PMDS)Thinking outside the box: a search for new genes responsible for Müllerian regression -GenOmics 2020
2021Amélie PITONIllkirchFoundation For Rare DiseasesIntellectual diasbility (ID)Analysis of parental genomes in individuals with intellectual disability without pathogenic mutation identified by solo WGS -GenOmics 2020
2021Amédée RENANDNantesFoundation For Rare DiseasesAutoImmune Liver Diseases (AILD)Tracking autoreactive CD4 T cells in rare autoimmune liver diseases -GenOmics 2020
2021Jean SOULIERParisFoundation For Rare DiseasesFanconi AnemiaDysfunctional hematopoietic stem cells and clonal hematopoiesis in Fanconi Anemia: what underlies an attenuated phenotype? -GenOmics 2020
2021Anne Claude TABETParisFoundation For Rare DiseasesAutismCharacterization of non recurrent duplications by next-generation optical mapping in patients with autism -GenOmics 2020
2021Angela TINGAUD-SEQUEIRABordeauxFoundation For Rare DiseasesOculo-Auriculo-vertebral spectrumWhole-genome sequencing in the complex Oculo-Auriculo-vertebral spectrum: application on whole-exome sequencing negative familial cases versus direct analysis -GenOmics 2020
2021Léon KAUTZToulouse Awards - Alnylam Pharmaceuticalsβ-thalassemiaTargeting the hepatokine ERFE-2 to decrease iron overload and improve anemia in β-thalassemiaBeta-thalassemia is a rare genetic disease affecting 1-9 people out of 1 million, caused by a defect in hemoglobin synthesis. The disease is characterized by profound anemia and iron overload, leading to severe, life-threatening clinical complications. Iron is an essential constituent of hemoglobin in red blood cells. Hepcidin is the central regulator of iron homeostasis. In anemia, erythroferrone regulates hepcidin production to ensure iron supply to the bone marrow for erythropoiesis. However, our data indicate that a second factor exerts a similar function. We have identified a novel hepcidin repressor (ERFE-2) whose expression is increased in the liver during repair of anemia or in beta-thalassemia, Our project aims to develop a strategy based on RNA interference (antisense oligonucleotides) to confirm the role of ERFE-2 in hepcidin regulation and the establishment of iron overload in beta-thalassemia, and to assess the therapeutic potential of ERFE-2 inhibition in a mouse model of the disease. The completion of this project will lead to the development of new therapeutic strategies based on the use of antisense oligonucleotides for the treatment of beta-thalassemia, for which current treatments are inappropriate and often ineffective.Alnylam Pharmaceuticals 2020 Award
2021Pierre-Louis THARAUXParisAwards - Alnylam PharmaceuticalsGlomerular DiseasesSILENT COLLAPSE: miRNome of human and experimental collapsing glomerulopathies and therapeutic proof of concept by miR-92a gene silencingCollapsing glomerulopathy (CGP) is a rare and very serious kidney disease that represents a scientific and medical challenge. CGP causes rapid destruction of the glomeruli, the structures in the kidney that filter blood plasma into urine. It is not possible to prevent this destruction in order to avoid renal failure. An abnormal change in the behavior of glomerular cells, the podocytes, is now recognized as the cause of the disease. Under normal conditions, podocytes are unable to proliferate and retain their differentiated phenotype. During PMC, podocytes revert to a developmental genetic program that includes down-regulation of cell cycle inhibitors and loss of mature cell markers. Our team recently observed that the loss of podocyte quiescence is caused by the appearance of a microRNA, miR-92a, in a CGP model and in patient biopsies. miR-92a inhibits the expression of a potent cell cycle inhibitor, p57, and inhibition of this microRNA limits podocyte proliferation in vitro. This project will study the glomerular expression of miR-92a and its molecular targets in human PMFs and in two mouse PMF models. We will block the action of miR-92a with a laboratory-validated anti-miR strategy to prevent and, more importantly, treat this severe disease.Alnylam Pharmaceuticals 2020 Award
2021Brigitte CHABROLMarseilleIRCEM Corporate FoundationRare neurological diseases, Rare inborn errors of metabolism, Rare endocrine diseases, Diaphragmatic hernia, Rare gastroenterological diseases, Rare genetic diseases, Rare anemias, Rare bleeding diseases, Marfan syndrome, Spina bifida, Cystic fibrosisEthical reflection on the creation of a Rare Diseases Area dedicated to patients and their familiesThe Plateforme d'Expertise Maladie Rares (PEMR-APHM), accredited in 2020 by the DGOS, forms a network between AP-HM's 93 accredited rare disease centers and the associations, diagnostic laboratories and research units to which they are attached. Its aim is to encourage cross-functional implementation of patient pathways and support for rare disease centers. It provides for the creation of a meeting place dedicated to rare diseases for patients and their families, similar to the ERI for cancer.
The installation of this new space in France for the medico-social support of people suffering from a rare disease and their families is envisaged on the basis of the operation of these ERIs and the medico-social system for rare cancers in Holland. It should encourage listening and exchanges between the PEMR-APHM, patients and relatives at the time of diagnosis, expert patients, partner patients, caregivers, members of associations and other citizens. It will provide information on law and health, and supportive care.
We propose to analyze the views of patients, caregivers, associations and healthcare professionals in advance, in order to provide answers to the following questions:
How will the system fit into the "disease trajectory" (according to the concept proposed by Pr A. L. Strauss in "La trame de la négociation - Sociologie qualitative et interactionnisme", 1992)?
When would this device be used as a recourse (temporality of interest in the device, in particular in relation to the moment of diagnosis)?
What would be the benefits and limitations of the device for people? In particular, we'll be looking at the potential relevance of information exchanges between peers (such as patient-patient, parent-parent), the contribution to the care relationship and to empowerment.
What kind of communication and organizational arrangements (opening days, resource persons) should be envisaged for the Espace?
The research project will be led by Pr Chabrol, in collaboration with Pr Le Coz and his team.
Funding from the Fondation Maladies Rares will enable us to recruit a Master 2 student for this study. The results will be used to define the resources and organization of this new space, with the drafting of a best practice guide.
Humanities and social sciences 9
2021Sylvain FEREZMontpellierFoundation For Rare DiseasesHereditary metabolic diseasesInvisible patients? A study of the reconfiguration of stigma in the school and work environment after lung transplantation in people living with cystic fibrosisThe TransMuco study aims to understand the post-lung transplant experiences of people living with cystic fibrosis. Drawing on the theoretical perspective of the "disability production process" and building on the results of the MQSP-Muco study conducted between October 2016 and December 2018, it will attempt to uncover the major obstacles and facilitators to social participation encountered after lung transplantation within two specific environments, school and the world of work. Its innovative aspects consist in taking into account the interactions between individual and environmental factors in the production of handicap situations, and in the hypothesis that lung transplantation does not necessarily lead to the disappearance of handicap situations experienced by patients, but rather to their transformation.
Initially, the study involved ten life-story and practice interviews, repeated at intervals of two or three months, on the individual and daily lives of the people interviewed after transplantation. We would like to propose a quantitative extension, involving the administration of Environmental Quality Measurement questionnaires (MQE Sco and Pro) to all adults with lung transplants of more than 1 year and less than 3 years, followed by the CRCM at Foch Hospital.
Three types of results are expected
- Identification of environmental factors that hinder or facilitate school and work participation after lung transplantation;
- Description of the socio-demographic characteristics of the eligible population followed by the Foch Hospital CRCM, and better characterization of the sample of ten people interviewed as part of the TransMuco study in relation to this group;
- Identification of factors outside the school and work environments that may have an impact on the experience of disability in these two environments after transplantation.
Patients, their families and associations will be able to support their comments on the defense of rights with the MDPH and other institutions, and propose differentiated systems and aids adapted to patients' specific needs. Finally, some of these results could be transferred to patients with other rare diseases who may require lung transplantation.
Humanities and social sciences 9
2021Christelle DUPREZLilleFoundation For Rare DiseasesRare systemic and autoimmune diseases / Hereditary angioedemas, Immunological thrombocytopeniaEmotional processes in adult patients with hereditary angioedema: a pilot study coupling self-reported and physiological measures Hereditary angioedema (HA) is a rare genetic disorder characterized by attacks of swelling. Due to the unpredictable and potentially fatal nature of the symptomatic attacks, particularly of the larynx, the emotional repercussions of the disease are significant (e.g., anxiety, depression, reduced quality of life). Emotions (e.g., fear, anxiety, stress) also play a role in triggering attacks. The clinical observation that HA patients have a somewhat atypical "profile" (minimization of disease severity, disillusioned optimism, detachment, "emotional placidity"), to be confirmed by studies such as the present project, suggests that either these patients activate adapted emotional regulation (ER) mechanisms to anticipate potential symptomatic crises, or they present ER difficulties, which can lead to ER disorders (e.g., difficulty differentiating and expressing emotions, or alexithymia). ER strategies and possible ER difficulties in patients with HA are still poorly studied, but recent data highlight in particular autonomic dysregulation (hyperactivity of the sympathetic system associated with parasympathetic hypoactivity in a stressful situation), compatible with the hypothesis of a specific or deficient ER in patients. The aim of the present project is to determine whether or not patients show an ER deficit, reflected in particular by the presence of alexithymia, using two complementary studies combining self-report measures (questionnaires assessing ER strategies, ER difficulties, alexithymia, anxiety-depression, and quality of life - ANGIORE QUANTI study) and physiological measures more reliable than those used in existing data (measurement of heart rate variability and electrodermal response using an Empatica E4 wristband in a psychological stress task). The results will be used to identify relevant variables that can eventually be taken into account in patient management. The data are intended to be supplemented by studies on larger samples, notably through recruitment via patient associations.Humanities and social sciences 9
2021Estelle LOUETParisFoundation For Rare DiseasesDevelopmental abnormalities and malformations / MyelomeningoceleIn utero surgery for fetal myelomeningocele: mechanisms of decision making and
psychological impact of prenatal therapy
Myelomeningocele (MMC) is a congenital malformation of the spinal cord and spine, leading to sensory and motor deficits in the lower limbs, sphincter disorders, and orthopedic and cerebral complications. In utero surgery to repair this malformation has been shown to improve the prognosis of children with MMC, compared with postnatal surgery. To date, very few studies have investigated the psychological impact of choosing in utero surgery on patients and their co-parents.
Objectives - The primary objective of our study is to investigate a posteriori the experience of couples who made the choice of fetal surgery for MMC repair.
The secondary objectives are as follows:
- To identify the factors that contributed to the choice of prenatal surgery rather than postnatal surgery or medical termination of pregnancy.
- Evaluate the quality of the information couples received regarding the three options offered in the face of a prenatal diagnosis of CMD: in utero surgery, postnatal surgery and medical termination of pregnancy.
- To explore ways of improving support for couples before and after fetal surgery to repair CMD.
Methodology - This is a cross-sectional observational study. Our approach will be mixed, qualitative and quantitative. Semi-structured interviews will be conducted with each couple, recorded and transcribed. Analysis will be based on two complementary qualitative methods: thematic analysis (Interpretative Phenomenological Analysis) and discourse analysis. A hetero-questionnaire on decision-making will also be given to the patients and their families, in order to relate its data to the themes obtained by the qualitative analysis.
Humanities and social sciences 9
2021Sandrine CARABEUXParisAssociatif (PraderWilli) / IRCEM Corporate FoundationDevelopmental anomalies and malformation syndromesTo explore a new mode of social intervention to improve support for people with PWS and other rare and complex disabilities. -Spouse with association
2021Hélène DOLLFUSStrasbourgAssociative (BBS)Sensory disorders (rare eye diseases and deafness)Development of innovative therapies to treat retinopathy pigmentosa associated with Bardet-Biedl Syndrome (collab. Deniz Dalkara) -Spouse with association
2021Marc BITOUNParisAssociative (PACS1)Developmental anomalies and malformation syndromesProof of concept of therapy by allele-specific silencing for the Schuurs-Hoeijmakers Syndrome -Spouse with association
2021Guy LENAERSAngersAssociative (AAP AMMi)Rare neurological diseases A pharmacological approach of the Leigh syndrome related to MTFMT recessive variants -Spouse with association
2021Alessandro PRIGIONEDusseldorfAssociative (AAP AMMi)Rare neurological diseases Modeling Leigh syndrome caused by MTFMT mutations using patient- specific neuronal cells -Spouse with association
2021Kevin LE DUCLilleAssociation (APEHDia)Developmental anomalies and malformation syndromesImpact of analgesia before intubation and intact cord resuscitation on cardiorespiratory adaptation at birth: study on a CDH newborn lamb's model. -Spouse with association
2021Jamila FAIVREVillejuifAssociative (ALBI)Rare hepato-gastroenterological diseasesImmune landscape in human primary sclerosing cholangitis -Spouse with association
2021Sara LEMOINNEParisAssociative (ALBI)Rare hepato-gastroenterological diseasesEffect of the probiotic Faecalibacterium prausnitzii in primary sclerosing cholangitis -Spouse with association
2021Amedée RENANDNantesAssociative (ALBI)Rare hepato-gastroenterological diseasesDirect effect of steroid hormone pathways on pathogenic T lymphocytes in autoimmune liver diseases. -Spouse with association
2021Ingrid BANOVICRouenAssociative (AAP HPN)Rare non-malignant hematological diseases Chronic Fatigue and Cognitive Functioning in Patients with HPN and AM -Spouse with association
2021David MICHONNEAUParisAssociative (HPN)Rare non-malignant hematological diseases Understanding the mechanisms of operational tolerance after hematopoietic stem cell allograft -Spouse with association
2021Céline LANCELOTAngersLes Ailes FoundationRare endocrine disordersTo better understand the social and emotional functioning of girls with Turner syndrome in order to better support them in their daily lives -Outside AAP
2021Françoise SCHMITTAngersLes Ailes FoundationRare hepato-gastroenterological diseasesLaparo-DAN Improving the diagnosis and care pathway for children with rare digestive malformations - A prospective study of antenatal diagnostic criteria for digestive complications of laparoschisis -Outside AAP
2021Clémence VANLERBERGHELilleCIC North WestDevelopmental anomalies and malformation syndromesDeciphering The Genetic Basis of Fibular Hypoplasia/ Agenesis - Functional Studies For Non Coding Variants -Outside AAP
2021Audrey LECOUFLELilleLes Ailes FoundationDevelopmental anomalies and malformation syndromesImproving the management of children with esophageal atresia -Outside AAP
2021Fabrice LEJEUNELilleLEJEUNEPulmonary rare diseasesCharacterization of new nonsense mutation corrector molecules -Outside AAP
2021Betty GARDIENantesGift of Mr Fournetvon Hippel-Lindau diseaseStudy of mutations identified in new exons of the VHL gene associated with polycythemia or VHL disease -Outside AAP
2021Betty GARDIENantesPGCD donationvon Hippel-Lindau diseaseCellular modeling of pathologies associated with VHL gene mutations -Outside AAP
2021Nicoletta DIASIOStrasbourgNovo NordiskDevelopmental anomalies and malformation syndromesThe hormonal factory of gender and age: between negotiations and medicalization of body variations - PHARMAGENREThis sociological study examines the effects of medicalization, which, in the absence of a cure, accompanies patients with genetic anomalies throughout their lives. Through interviews with women of three age groups, and observations in local care centers and an association, we study the individual and social effects of biomedical devices on life courses. This syndrome enables us to analyze a "biotechnical continuum" articulating prenatal screening, hormonal treatments and medically assisted procreation.Outside AAP
2021Roland LIBLAUToulousePatron of the Rare Diseases FoundationRare systemic and autoimmune disordersHUMAN IMMUNE SIGNATURES OF NARCOLEPSY WITH CATAPLEXY (2021) -Outside AAP
2021Pascale QUIGNONRennesGroupama Loire BretagneRare neurological diseases Genetic research in canine epilepsies as models for human epilepsies -Outside AAP
2021Jérome DINETNancyIRCEM Corporate FoundationRare non-malignant hematological diseases HEMOGAME Co-design of a serious game prototype for children with bleeding disorders, their parents and teachers -Outside AAP
2021Dan ISTRATECompiègneFoundation For Rare DiseasesOther rare diseasesDEDALE : Tool to facilitate access to medico-social assistance by expressing the patient's needs -Outside AAP
2021Guy LENAERSAngersSODEBO FoundationOther rare diseasesInterest of micro-nutrition for the treatment of rare diseases -Outside AAP
2022Kim MINCHULIllkirchFoundation For Rare DiseasesTubular aggregate myopathy (TAM)Tracking the origin of tubular aggregate myopathy by single-nucleus transcriptomics -GenOmics 2021
2022Djihad HADJADJParisFoundation For Rare DiseasesPredisposition to familial midgut carcinoid tumors (FMCT).

Predisposition to neuroendocrine tumors.
Identification of constitutional genetic abnormalities predisposing to Familial midgut carcinoid tumors -GenOmics 2021
2022Marion DELOUSLyonFoundation For Rare DiseasesTaybi-Linder Syndrome, TALS or Microcephalic Osteodysplastic Primordial Dwarfism type I (MOPDI), OMIM 210710
Roifman Syndrome, RFMN, OMIM 616651
Lowry-Wood Syndrome, LWS, OMIM 226960
2022Stéphane VIVILLEStarsbourgFoundation For Rare DiseasesInfertility
Male infertility
Non-obstructive azoospermia
Deciphering genetic causes of non-obstructive azoospermia via exome sequencing; a way to personalize treatments and to develop new diagnostic tools. -GenOmics 2021
2022Audrey PUTOUXLyonFoundation For Rare DiseasesAnencephalyTowards the identification of genes involved in recurrent anencephaly -GenOmics 2021
2022Marie-Louise FREMONDParisFoundation For Rare DiseasesRheumatoid factor positive arthritis
Type I interferonopathies
Identifying Novel Monogenic Interferon-Mediated Juvenile Rheumatoid Arthritis -GenOmics 2021
2022Xavier PUECHALParisFoundation For Rare DiseasesWhipple diseaseDeciphering genetic and molecular bases of Whipple disease -GenOmics 2021
2022Sandrine VUILLAUMIER-BARROTParisFoundation For Rare Diseasescongenital disorder of glycosylationResearch of homozygous variant in 5' or 3'UTR ALG12 region or cis regulating elements by whole genome for one ALG12-CDG suspected patient -GenOmics 2021
2022Céline HUBERParisFoundation For Rare DiseasesChondrodysplasias with multiple dislocations (CMD) form a group of severe disorders including :
-Desbuquois dysplasia type 2 (MIM: 615777/AR)
-Neonatal short limb dysplasia (MIM: -/AR)
-Ehlers-Danlos syndrome (EDS) progeroid variant or EDS spondylodysplastic type 1 (EDSSPD1), including Larsen syndrome, la Reunion variant (MIM: 130070/AR)
-Spondyloepimetaphyseal dysplasia with joint laxity, Beighton type (MIM: 271640/AR) or EDS spondylodysplastic type 2 (EDSSPD2) (MIM: 615349/AR)
-Larsen-like syndrome (MIM: 245600/AR)
-Joint dislocations and skeletal dysplasia, Desbuquois-like (MIM: 618870/AR)
-Temtamy preaxial brachydactyly syndrome (TPBS) (MIM: 605282/AR)
-Ehlers-Danlos musculocontractural syndrome type 2 (MIM: 615539/AR)
-Diastrophic dysplasia (MIM: 222600/AR)
-Recessive Larsen syndrome or spondyloepiphyseal dysplasia with congenital joint (MIM: 143095/AR)
-Ehlers-Danlos syndrome musculocontractural type 1 (MIM: 601776/AR)
-Chondrodysplasia with joint dislocations, gPAPP type (MIM: 614078/AR)
-Multiple congenital malformation syndrome including vertebral malsegmentation and joint dislocations (MIM: -/AR)
-Skeletal dysplasia, osteoporosis, multiple dislocations and amelogenesis imperfecta (MIM: 618363/AR)
-Desbuquois dysplasia type 1, including Kim variant (MIM: 251450/AR)
-Recessive multiple epiphyseal dysplasia (MIM: 617719/AR)
-TMEM-CDG (MIM: 614727/AR)
Identification of new pathogenic variants in individuals with Chondrodysplasias with multiple dislocations (CMD) combining WGS and RNASEQ -GenOmics 2021
2022Régis GIETRennesGroupama Loire BretagneRare infantile epileptic and developmental encephalopathyFunctional study of TACC1, a new gene involved in a rare form of infantile Epileptic and Developmental Encephalopathy -Outside AAP
2022Izabela SUMARAIllkirchFoundation For Rare DiseasesFragile X syndromeTherapeutic dissolution of aberrant nucleoporin condensation in Fragile X syndrome using small molecule inhibitorsNuclear pores (NPs) are the only gateways between nucleus and cytoplasm, ensuring cell function and survival. We have discovered a novel pathway by which FMRP directs the spatial assembly of nucleoporins at the nuclear envelope to form functional NPs. In the absence of FMRP, nucleoporins assemble aberrantly in the cytoplasm into aggregate-like structures, and the transport function of NPs is disrupted. Models of the rare disease fragile X syndrome (FXS), in which FMRP is absent, show the same nucleoporin aggregates, suggesting that these defects may contribute to the pathology of this disease. FXS is the most common form of hereditary mental retardation, for which there is currently no treatment. We hope our results will create a basis for the future development of new gene therapy strategies to cure this disease.High throughput screening / Hit to lead 2021
2022Marco PONTOGLIOParisFoundation For Rare DiseasesHNF1B-Cakut (Congenital abnormalities of the Kidney and the Urogenital tract
HNF1B-ADTKD (Autosomal Dominant Tubulo-Interstitial Kidney Disease)
A pharmacological therapy for HNF1B-deficiencyChronic kidney disease (CKD) is characterized by the progressive decline of renal function towards end-stage renal failure. Some rare forms of CKD are caused by mutations in a gene called "Hepatocyte Nuclear Factor 1 beta" HNF1B, which codes for a nuclear protein that plays an important role in the expression of many kidney genes. Patients with mutations in this gene develop renal failure, which can be severe. There is currently no pharmacological treatment available for these patients, who often end up needing dialysis or transplantation.
An important feature is that these patients are heterozygous for mutations that nullify HNF1B activity. Interestingly, these patients still carry a wild-type allele for HNF1B. We believe that in these patients there is a haploinsufficiency that will result in insufficient biological activity of HNF1B. This raises the possibility that a pharmacological treatment capable of stimulating residual activity in these patients could play a beneficial role in the treatment of the disease.
The aim of this research project is therefore to validate the use of certain chemical compounds which have been shown to increase HNF1B transcriptional activity. To do this, we have a mouse model that is deficient in HNF1B, which will enable us to validate our compounds.
High throughput screening / Hit to lead 2021
2022Barbara BARDONIValbonneFoundation For Rare DiseasesFragile X Syndrome
Autism Spectrum Disorder
Intellectual disability
Identification of drug candidates to treat the Fragile X SyndromeFragile X syndrome (FXS) is a rare disorder (ORPHA908) (1/4000 males and 1/7000 females). The syndrome is characterized by intellectual disability of varying severity, facial dysmorphia and macro-orchidism in males. However, patients may also present behavioral disorders (hyperactivity, autistic behavior), language delay, sleep disorders and epileptic seizures. Today, FXS is also considered the most common form of hereditary autism spectrum disorder.
The syndrome is due to the absence of the FMRP protein, an RNA-binding protein thought to be involved in controlling the translation of proteins involved in nervous system development.
No specific therapy is currently available to treat this disease. There is therefore a need to identify new drugs for this disease that can act singularly or in combination with other drugs, so that they can be administered to patients at different stages of their lives and thus alter the trajectory of this very serious disease.
To this end, we have generated a model cell line for the disease. We have already used this cell line to screen a collection of drugs, and have identified a drug - SM4 - which has the capacity to improve the altered morphology of the cells in the model line. Moreover, administration of this drug to mice - which are FXS models - improves their socio-cognitive deficits. In order to increase the number of molecules that can be used to treat FXS, we are going to carry out a new screening using two new collections of bioactive molecules with the same strategy that already gave positive results in the first screening.
From a molecular point of view, it has been shown that other forms of intellectual disability and/or autism spectrum disorders share the same abnormalities as FXS. For this reason, it may be hypothesized that drugs developed to treat FXS could subsequently also be used successfully to treat other diseases characterized by intellectual disability and/or autism spectrum disorder.
High throughput screening / Hit to lead 2021
2022Mahel ZEGHOUFSaclayFoundation For Rare DiseasesX-linked non-syndromic intellectual disability (ORPHA:777)
IQSEC2-related syndromic intellectual disability (ORPHA:397933)
High Throughput Screening of IQSEC2 activity modulators: towards new pharmacotherapeutic approaches in X-linked intellectual disability (SCREENXLID)X-linked intellectual disabilities (XLIDs) are a heterogeneous group of over 200 rare disorders that share the common feature of varying degrees of intellectual impairment associated with impaired adaptive behaviors, and manifest in childhood, predominantly in boys. More than 70 different mutations in the IQSEC2 gene have been associated with multiple XLIDs with associated symptoms such as epilepsy and autism. These mutations result in the loss of the IQSEC2 protein or the production of deregulated forms, whose activity is either increased or decreased.
A major challenge in treating these diseases is to discover molecules that target the defective proteins precisely and effectively. Such molecules are sorely lacking both in basic research as tools to better understand the biological function of IQSEC2 during brain development, and as starting points for the development of new therapies. For this, a sensitive, robust and miniaturized assay is needed to efficiently test a large number of compounds.
We are able to reconstitute the activity of the IQSEC2 protein on artificial membranes which mimic those of cells. Introducing membranes into the assay is an original approach, as it reproduces as closely as possible the conditions required for the protein to function properly in the cell. To observe the activity of the IQSEC2 protein, we look at changes in the fluorescence of its target Arf, a light emission that increases when it changes shape following activation. Fluorescence has the advantage of being highly sensitive, enabling precise quantification of this activation over time. Our initial results indicate that the miniaturization of this assay on an artificial membrane is possible, an essential step if we are to be able to test a large number of chemical compounds. The aim of the SCREENXLID project is to automate this assay in miniaturized form in order to screen a library of around 10,000 natural or chemical compounds. Compounds capable of modifying IQSEC2 activity will be ranked according to their efficacy and subjected to a second, more robust screening for validation. We will select compounds capable of either increasing or decreasing IQSEC2 activity. The best candidates will be selected on the basis of their physico-chemical properties, which will enable us to predict potential toxicity, administration possibilities and future optimization.
The SCREENXLID project will discover small molecules capable of modifying the activity of the IQSEC2 protein, either by acting directly on its activity or on its ability to bind to the membrane, a binding essential for its activity. Such molecules will be powerful tools for better understanding how IQSEC2 functions, and for explaining defective mechanisms in XLID-associated mutants. Their detailed characterization in cellular and animal models will open up new prospects for the development of personalized therapeutic strategies, bringing help and hope to affected children and their families.
High throughput screening / Hit to lead 2021
2022Cécile VOISSETBrestFoundation For Rare DiseasesCreutzfeldt-Jakob disease (CJD)
Gerstmann-Sträussler-Scheinker (GSS) syndrome
Fatal familial insomnia (FFI)
Identification and structural optimization of novel first-in-class anti-prion compoundsCreutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia are rare neurodegenerative diseases known as spongiform encephalopathies. Creutzfeldt-Jakob disease (CJD) affects one person per million population per year, or 100 to 150 cases per year in France. The first symptoms of CJD are often non-specific, such as depression or anxiety. This is followed by problems with memory, orientation and language. This dementing syndrome is progressively associated with involuntary muscle spasms, disturbances of balance or vision, tremors and epileptic seizures. CJD is the only human disease that can be either sporadic (80%), genetic (15%) or acquired through contamination (<5%). Les cas sporadiques apparaissent en moyenne vers l'âge de 60 à 65 ans. Le syndrome de Gerstmann–Sträussler–Scheinker touche entre 1 à 10 personnes pour 100 000 000. Ce syndrome est d’origine génétique. L'insomnie familiale, qui a une prévalence <1 > Using an original screening method based on [PSI+] and [URE3] prions from the baker's yeast S. cerevisiae, we have in the past identified several compounds active against prions from drug libraries with marketing authorization. Most of the anti-prion drugs identified by this approach were found to be active against the mammalian prion PrPSc in different cell models, and also in vivo in a mouse model of prion disease. These results indicate that yeast prions are good models for identifying compounds active against the PrPSc prion affecting humans.
The screening strategy proposed by C. Voisset's group (Brest Faculty of Medicine) involves testing the ability of the 3,800 molecules in the JUNIA's library to eliminate yeast prions. Molecules capable of eliminating prions from yeast will then be tested for their ability to eliminate the PrPSc prion. The most promising anti-prion molecules thus identified will then be modified by A. Ghinet's team of chemists (JUNIA Grande Ecole d'Ingénieurs, Lille) to improve their activity.
The proposed screening program will make it possible to identify new anti-prion compounds and thus new therapeutic avenues for patients suffering from prion diseases for which no therapeutic solution is currently available.
High throughput screening / Hit to lead 2021
2022Alice LEPELLEYParisFoundation For Rare DiseasesRare bone diseasesCharacterisation of the role of IFN signalling in neural cells in ATAD3A diseaseNeurodegenerative diseases are increasingly associated with abnormal brain inflammation, the origin of which is poorly understood. Type I interferons represent the first line of defense against viruses. However, type I interferonopathies are rare genetic diseases associated with an inappropriate increase in interferon signaling, often leading to neurological pathology. To better understand the presence and consequences of abnormal interferon levels on neuropathology, we propose to generate brain cell models of patients with type I interferonopathy. These models will be studied as part of a research project. Their study will enable us to design and test therapeutic strategies that are also relevant to more common neurological diseases.Models 2022
2022Florian LESAGENiceFoundation For Rare DiseasesRare neurological diseases, Developmental anomalies and malformation syndromesMouse models of human Birk Barel syndromeBirk-Barel syndrome (BBS) is a rare genetic disorder combining hyperactivity and mental retardation. The 15 mutations identified are all located in KCNK9, one of the rare genes subject to parental imprinting, with only the copy inherited from the mother being active. KCNK9 codes for the TASK3 ion channel. BBS mutations increase or decrease TASK3 activity. We have shown that gene inactivation of TASK3 is associated with learning difficulties and hyperactivity in mice, and that re-expression of the paternal gene by inhibitors of enzymes involved in parental imprinting corrects these symptoms. We propose to prepare mice carrying BBS mutations, either activating or inhibiting, and to verify that these mutations cause BBS symptoms. Once validated, these mice will be used to study disease mechanisms and test new therapeutic strategies adapted to the different mutation types.Models 2022
2022Sarah BECK-CORMIERNantesFoundation For Rare DiseasesRare neurological diseasesGeneration of a new mouse model for the rare PFBC diseasePrimary cerebral calcification (PCC) is a rare neurological disorder characterized by calcium and phosphate deposits in the blood vessels of the brain. Why these deposits form remains an unanswered question, and there is no treatment to prevent them or cure the disease. However, recent research has uncovered mutations in the genes responsible for this disease. The aim of our project is to understand why and how mutations in these genes induce calcifications. To this end, we aim to create a model for studying the human disease by reproducing in mice the XPR1 gene mutation most frequently found in patients. We will call on the Institut Clinique de la Souris to generate this model. The study of these mice will enable us to elucidate the mechanisms at the origin of MCC and its evolution, and provide leads for the development of new treatments.Models 2022
2022Justine MASSONParisFoundation For Rare DiseasesRare neurological diseasesCortical and cerebellar organoids, new models to study a rare neurodevelopmental disease caused by mutations in the YIF1B geneThe ciliopathies represent a group of rare diseases affecting the brain and caused by dysfunction of a highly specialized cellular organelle, the cilium. Ciliopathies are genetic diseases, and patients carry mutations in genes essential for cilium function. We have identified patients with mutations in a gene encoding an intracellular trafficking protein and suffering from ciliopathic neurological abnormalities. We have demonstrated that loss of function of this protein affects brain anatomy in a mouse model. In addition, we showed that ciliogenesis (the ability of cells to develop a cilium) was abnormal. As the mouse model does not recapitulate all the cerebral alterations observed in patients, our project aims to study the cellular processes affected by the loss of function of this protein by developing cerebral organoids, tiny self-organizing three-dimensional tissue cultures derived from patient stem cells that mimic cerebral structures.Models 2022
2022David HICKSStrasbourgFoundation For Rare DiseasesSensory disorders (rare eye diseases and deafness)Creation of a diurnal rodent model of Stargardts Disease STGD1Stargardts disease (SD) is a rare form of progressive blindness that manifests itself in childhood, leading to irreversible loss of sight and suffering. There is no treatment to limit or cure this disease, and existing animal models (mice) do not faithfully reflect human symptoms. Indeed, mice have no macula and few cone photoreceptors, the cell type mainly affected. We propose that diurnal rodents, which have 10 to 15 times more cones than mice, are better models. Recently, we have shown that blocking the SD causal gene, known as abca4, in these animals creates retinal degeneration similar to that in human patients. We aim to extend these results to model different forms of the disease and distribute the animals to other institutes.Models 2022
2022Stéphanie TRUDELToulouseFoundation For Rare DiseasesRare neurological diseasesGeneration and characterization of iPSCs from Sanfilippo type B patients fibroblastMucopolysaccharidosis type III (MPS III) is a disease in which patients have a defect in the function of lysosomes, which are involved in the degradation of heparan sulfates (HS). HS accumulation is at the root of neurological disorders in these patients. However, the molecular mechanisms underlying neurodegeneration are not yet fully understood. No treatment is available, but clinical trials are underway to deliver the deficient enzyme to the brains of MPS III patients. To carry out research into therapies and pathophysiology, we need good models of the disease. But in the case of MPS IIIB, we are faced with a lack of human models. The aim of this project is to obtain pluripotent stem cells from MPS IIIB patient cells and transform them into brain cells in order to develop new therapies and better understand this disease.Models 2022
2022Matthieu GIRAUDNantesFoundation For Rare DiseasesRare systemic and autoimmune disorders, Immune deficiency disordersA new rat model of deficient anterior pituitary gland with variable immune deficiency syndrome by mutation of the NFKB2 geneThe variable immune deficiency-pituitary insufficiency syndrome or DAVID syndrome is a rare genetic disorder combining early common variable immune deficiencies, causing recurrent and severe infections, and later symptomatic endocrine deficiencies, such as pituitary hormone deficiency. Studies have reported that patients with this syndrome have specific mutations in the NF-kB2 gene.
We aim to generate a rat model carrying one of these mutations to reproduce the symptoms observed in these patients. This animal model will enable us to study in greater detail the role of pathways involving NF-kB2 in the function of certain immune system populations, in autoimmunity processes and in certain neuro-endocrine functions. Ultimately, this model could be useful for identifying new therapeutic strategies in the context of autoimmune or inflammatory diseases.
Models 2022
2022Anne-Cécile REYMANNStrasbourgFoundation For Rare DiseasesRare neurological diseases, Other rare diseasesCRISPR targeted mutagenesis of C. elegans actin: novel insights into the understanding of human non-muscle actinopathiesWith a team of scientists, we are deciphering the fundamental mechanisms behind the symptoms in relation to spontaneous de novo genetic variations in an essential cytoskeletal gene, actin, corresponding to the rare disease known as non-muscular actinopathies. My team is specifically using the model organism C. elegans, a soil nematode a few millimetres long, to reproduce the same variants found in some patients in order to explore the consequences at different scales in a simpler living model system but with an almost identical set of cytoskeletal proteins. Data obtained from experiments at several scales - molecular, cellular, organism, patient - are compared to better characterize the mechanisms leading to pathological conditions and the causes of symptoms in humans. Our ultimate goal is to lay the foundations for future clinical studies and provide widely applicable functional tests for establishing genotype-phenotype correlations.Models 2022
2022Valérie ALLAMANDParisAFM TelethonNeuromuscular disease, connective tissue disordersSuppression of premature termination codons by anticodon-edited tRNAsAt least 10% of mutations responsible for human genetic diseases are nonsense mutations, affecting a single base of a gene sequence and creating a premature stop codon (PTC). The presence of a PTC can lead to the synthesis of a shorter protein, often non-functional and deleterious, or to the absence of protein synthesis as transcripts are degraded by nonsense-mediated decay (NMD).
The aim of the proposed project is to counteract the effect of nonsense mutations and restore protein synthesis, using modified transfer RNAs (tRNAs). This strategy replaces the PTC with the correct amino acid, without altering the natural stop codons. As the same modified tRNA can correct PTCs in any gene, this approach will benefit a large number of genetic diseases.
The project focuses on several rare diseases: neuromuscular (collagen VI and laminin alpha2 related, Duchenne muscular dystrophy, laminopathies), classical Ehlers-Danlos syndromes and a metabolic disease (Pseudoxanthum elasticum). We will evaluate the efficacy of modified tRNAs alone or in combination with NMD inhibitors, in vitro in patient cells, and in vivo in animal models.
This project will provide robust proof of concept to propose an innovative therapeutic response for these diseases for which no treatment currently exists.
Therapeutic proofs of concept 2021
2022David BONNAFEOrsayAFM TelethonSjögren's Syndrome, Rare systemic and autoimmune disordersA new way of targeting IFN-g for ocular dryness of primary Sjögren's
Syndrome: towards eye-drops of glycomimetics endowed with nanomolar
anti-IFN-g activities.
Primary Sjögren's Syndrome (pSS) is a rare autoimmune disease affecting the glandular epithelium, mainly the salivary and lacrimal glands. It leads to dry mouth and eyes, pain and fatigue that severely impact patients' quality of life. Systemic complications occur in 30-50% of patients. To date, there is no validated treatment for systemic pSS, and no specific treatment for dry mouth and dry eyes has been developed to treat dryness syndromes.
Experts in the synthesis of cytokine-targeted glycomimetics and clinicians from a pSS reference center propose to combine their expertise and strengths to address this patient need. Based on respective previous work: identification of glycomimetics with nanomolar anti-IFN- g activities in vitro and identification of a deleterious activation loop involving IL-7 and IFN-g as a characteristic dysfunction in pSS, we propose to: i. establish the therapeutic potential, in the context of pSS, of direct targeting of IFN-g by a glycomimetic; ii. improve the potency and selectivity of our anti-IFN-g hit validated in vitro. The physico-chemical properties of the target molecules mean that they can be formulated as eye drops, a significant advantage for subsequent first-line development as a treatment for pSS-associated dry eye syndrome.
Therapeutic proofs of concept 2021
2022Cécile CONTIN-BORDESBordeauxAFM TelethonSystemic Sclerosis, Rare systemic and autoimmune disordersEndothelial cell-induced macrophages efferocytosis alteration during Systemic Sclerosis: mechanistic dissection and new therapeutic intervention to limit fibrosis.Systemic scleroderma (SSc) is an incurable fibrotic autoimmune disease affecting almost 10,000 people in France. Treating fibrosis in SSc is a major medical challenge. Uncontrolled inflammation promotes deregulation of the tissue repair process and contributes to fibrosis during SSc. Efferocytosis is essential to limit inflammation and promote controlled tissue repair. Our group has shown that platelet-mediated activation of endothelial cells plays a major role in the pathophysiology of SSc. IL-1β-activated endothelial cells promote fibrosis by inducing a cytokine microenvironment capable of differentiating DC-SIGN+ macrophages with pro-inflammatory functions. DC-SIGN+ macrophages have impaired efferocytosis capacity, and the expression of efferocytosis-associated genes is altered in the skin of ScS patients. Our industrial partner has developed an innovative treatment composed of pro-resolving factors produced by efferocytic macrophages capable of controlling inflammation and promoting normal tissue repair. The objectives of this project are (i) to understand the mechanisms by which endothelial cells and platelets alter the efferocytosis capacities of macrophages (ii) to propose innovative treatments aimed at compensating for efferocytosis defects to limit inflammation and fibrosis in ScS.Therapeutic proofs of concept 2021
2022Isabelle MARTYLa TroncheAFM TelethonNeuromuscular diseaseNanoblades as a genome editing tool for neuromuscular disordersGene editing is a promising approach for myopathies, particularly those linked to RYR1, as this gene is too large to be inserted into a viral vector as tested in other myopathies. Different strategies are currently used to introduce gene-editing tools into muscle cells and remove a DNA fragment, each with its advantages and disadvantages. The current method of choice uses viral vectors with high transduction efficiency but the disadvantage of importing foreign DNA into the target cell, which can lead to damaging integration into the genome. The aim of this project is to determine the in vitro efficacy of a new method compared with reference viral and non-viral methods, and its potential for improvement for future in vivo use: i) transfer of the CAS9 gene and gRNAs by lentivirus, routinely used at GIN (reference viral method), ii) electroporation of ribonucleoproteins (RNPs) with Cas9 protein and gRNAs, routinely used at INMG (reference non-viral method), iii) transduction of "Nanoblades", viral pseudoparticles loaded with Cas9-gRNA RNPs without any gene transfer, developed at ENS. The project will be carried out using immortalized patient cells previously used to establish the POC of exon skipping efficiency. The function of the corrected protein will be assessed by calcium imaging.Therapeutic proofs of concept 2021
2022Olivier TABARYParisAFM TelethonCystic Fibrosis, Other rare diseasesDevelopment of a new microRNA therapeutic approach for the treatment
of all patients with Cystic Fibrosis
Cystic fibrosis is the most common hereditary disease in Caucasian populations. It is estimated that around 200 children with cystic fibrosis are born each year in France. The CFTR (Cystic Fibrosis Transmembrane conductance Regulator) gene responsible for the disease codes for the CFTR protein, which regulates chloride ion transport. Respiratory abnormalities are the main cause, but other organs are also affected.
Patients benefit from symptomatic treatments and, in recent years, curative therapies that target the CFTR channel. However, there is still an unmet clinical need for therapies for patients with mutations that are not compatible with these drugs, such as class I patients, who account for 10% of patients plus non-responders.
Antisense oligonucleotides (ASOs) offer new avenues for the development of personalized treatments for certain hereditary diseases, including cystic fibrosis. We have developed an ASO oligonucleotide TMEM16A which increases the expression and activity of the chloride channel anoctamin 1 (TMEM16A), and which can constitute an alternative channel to CFTR in all cystic fibrosis patients regardless of their mutations.
The aim of this project is to test the efficacy of the TMEM16A ASO on cells from patients and mice whose mutation does not allow them to benefit from curative treatments.
Therapeutic proofs of concept 2021
2022Isabelle TALONStrasbourgAFM TelethonDevelopmental anomalies and malformation syndromesPediatric mesh innovation with 3D bioprinting process : the first prosthesis
design for children
Several rare childhood diseases are characterized by a defect, such as congenital diaphragmatic hernia, esophageal atresia or giant omphalocele. There is no ideal replacement biomaterial for these rare pathologies, and children may require several major surgeries with high morbidity. Biodegradable prostheses have little place in infants, due to their rapid degradation and lack of sufficient tissue renewal at the end of this resorption. The polytetrafluoroethylene prosthesis currently used for the diaphragm and any other non-absorbable prosthesis do not meet the biomechanical criteria for pediatric implantation with high growth potential.
We are working on an already patented biodegradable albumin-based prosthesis (originally designed for other clinical applications) and an electrospun urethane-based synthetic prosthesis specifically designed for children. We are combining these two innovative biomaterials with 3D bioprinting of different cell types to optimize early tissue colonization and, above all, achieve genuine regeneration of the organ and its function. The objectives of this new stage of our research are threefold:
- Optimize the architectural characteristics of our prostheses,
- Evaluate the impact of printing architecture on colonization, - Find the best ratio between different cell types.
Therapeutic proofs of concept 2021
2022Christine LEAUTE-LABREZEBordeauxAwards - Alnylam PharmaceuticalsSturge-Weber syndrome, Dermatological diseases RNA interference approach targeting the GNAQ gene mutation in vascular anomaliesOur research team has extensive experience in developing innovative therapies for rare skin diseases and vascular anomalies. Our work has led to the filing of 2 patents on the treatment of infantile hemangiomas and the prevention of tumors in "moon children" (Xeroderma Pigmentosum). Since the discovery of the efficacy of propranolol in Bordeaux by Dr Christine Léauté-Labrèze, the treatment has been validated in many countries around the world, enabling the successful treatment of severe infantile hemangiomas. Today, with the Centre de Référence des maladies rares de la peau, we wish to invest in an unresolved issue - the treatment of vascular anomalies of genetic origin, such as angiomas planus - and propose an innovative therapeutic approach that targets the mutations present in the diseased zone visually delimited by the angioma. To ensure that this treatment targets the diseased cells without affecting other skin cells, we will develop an interfering RNA approach. This is the approach that holds the greatest therapeutic promise for these sometimes disfiguring diseases, with a major impact on patients for whom no satisfactory solution exists.Alnylam Pharmaceuticals 2022 Award
2022Nicolas PENELLilleAwards - APICIL FoundationRare cancersProspective clinico-biological database of desmoid tumors Desmoid tumors (ORPHA:873) are rare benign tumors (less than 400 cases/year in France), diagnosed around the age of 40 and affecting women 4 times more frequently than men. They can appear under the skin, on the abdomen, arms, legs, chest, neck or deeper in the belly. These tumors present 2 important clinical characteristics: their evolution cannot be predicted, and they are painful.
ALTITUDES is a prospective clinico-biological database that has included 630 patients with incidental cases of desmoid tumors. Recruitment has been completed and we are now starting the various sub-projects. In this study, we prospectively collected pain (visual analog scale), quality of life (QLQ-c30), anxiety/depression (HADS), employment status, marital status and income at inclusion (diagnosis), on an annual basis and in the event of a tumor event (relapse, progression, etc.). The ALTITUDES_TR2 project has 4 objectives, aimed at estimating the frequency of pain, identifying associated factors, assessing whether pain is associated with a higher risk of disease relapse/progression, and comparing the outcome of pain and non-pain patients.
This is an ancillary and exploratory project (ALTITUDES_TR2) in the human and social sciences of the ALTITUDES study.
Fondation APICIL 2022 Prize
2022Pierre-Olivier FERNAGUTPoitiersAssociation (ARAMISE)Rare neurological diseases Alpha-synuclein and the fate of oligodendrocytes in Multiple System Atrophy -Spouse with association
2022Nathalie JONCAToulouseAssociative (AIF)Dermatological diseases RARESKINLIP: Innovative in vitro models of ichthyosis to assess the efficiency of a novel lipid substitutive therapy in the rescue of the epidermal barrier -Spouse with association
2022Dimitri MOREAUGenevaAssociative (PACS1)Developmental anomalies and malformation syndromesDevelopment of a robust cell-based microscopy assay for compound screening project on PACS1 (R203W) rare disease -Spouse with association
2022Gaëlle BOUGEARDRouenAssociative (Li-Fraumeni)Rare cancersTP53 wt allele as a modifier factor in Li-Fraumeni syndrome -Spouse with association
2022Hamid-Reza REZVANIBordeauxInternational Order of AnysetiersDermatological diseases Modelling of pigmentary abnormalities in xeroderma pigmentosum type c (XPC) -Outside AAP
2022Alban BARUTEAUNantesIRCEM Corporate FoundationCardiovascular diseasesOSCAR: Outil de Suivi CARdiop diatrique domicile -Outside AAP
2022Lucile SESEParisOXYVIEPulmonary rare diseasesRole of socio-economic and environmental factors on the natural history of idiopathic pulmonary fibrosis: EXPOSOMFPI -Outside AAP
2022Guillaume CANAUDParisIRCEM Corporate FoundationHypergrowth syndromesPIK3CA is the therapeutic target of choice for vascular malformations associated with mutations in the RAS pathway -Outside AAP
2022Damien BREZULIERRennesGroupama Loire BretagneConnective tissue disordersValidation of a porcine model of bone defects in growth sites for reconstruction -Outside AAP
2022Gaëlle BOUGEARDVillejuifPatron of the Rare Diseases FoundationLi-Fraumeni syndromeTechnological innovation for improved management and treatment of Li-Fraumeni syndrome -Outside AAP
2023Stéphanie TOMEParisFoundation For Rare DiseasesNeuromuscular disorders / Myotonic dystrophy type 2Accurately characterizing the DM2 locus in patients using Oxford Nanopore technologies -GenOmics 2022
2023Piera SMERIGLIOParisFoundation For Rare DiseasesNeuromuscular disorders / Spinal Muscular Atrophy (SMA)EpiSMA: Profiling the Epigenetic Landscape of Spinal Muscular Atrophy (SMA) patients to understand phenotypic variability of muscle atrophy -GenOmics 2022
2023Béatrice PARFAITParisFoundation For Rare DiseasesDermatological diseases, Rare bone diseases / Congenital Pseudarthrosis of the TibiaMolecular bases of non-NF1 associated congenital pseudarthrosis of the tibia -GenOmics 2022
2023Sylvie MAZOYERLyonFoundation For Rare DiseasesDevelopmental anomalies and malformation syndromes, Immune deficiency disorders, Dermatological diseases / Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) or Taybi-Linder syndrome (TALS), Roifman syndrome (RFMN), Lowry Wood syndrome (LWS), OMIM 226960Long-read single cell sequencing to better characterise minor splicing defaults in RNU4ATAC associated diseases -GenOmics 2022
2023Pauline MARZINParisFoundation For Rare DiseasesConnective tissue disorders / Stiff skin syndromeElucidation of molecular bases of stiff Skin Syndrome: identification of new genes in pre-screened patients -GenOmics 2022
2023Aurélie DE THONELParisFoundation For Rare DiseasesRare neurological diseases / Rubinstein-Taybi syndrome Modelling Rubinstein-Taybi Syndrome: GenOmics of a rare, monogenic disease to address the
therapeutic potential of stress response pathways in neuronal disorders
-GenOmics 2022
2023Aude MAGERUSParisFoundation For Rare DiseasesRare systemic and autoimmune disorders / Autoimmune hepatitisGenetics of autoimmune hepatitis -GenOmics 2022
2023Benoit MIOTTOParisFoundation For Rare DiseasesDevelopmental anomalies and malformation syndromes / Meier-Gorlin SyndromePan-tissue transcriptional analysis of ORC1 regulated genes in a mouse model of Meier-Gorlin Syndrome -GenOmics 2022
2023Florence ROUCHER-BOULEZLyonFoundation For Rare DiseasesRare endocrine disorders / Primary Adrenal Insufficiency (PAI), Intra Uterine Growth Restriction (IUGR), Variation of Sex Development (VSD)Molecular Etiologies of Syndromic Presentation of Adrenal Insufficiency with Growth Restriction (MESPAG) -GenOmics 2022
2023Amélie PITONStrasbourgFoundation For Rare DiseasesNeurodevelopmental disordersValidation of the splicing factor RBMX2 as a novel gene involved in X-linked neurodevelopmental disorders -GenOmics 2022
2023Caroline DESOMBRELilleFoundation For Rare DiseasesRare chromosomal diseasesSCOlarization of children with rare chromosomal abnormalities: Levers and obstacles from the perspective of parents and teachersThe education of disabled students is a real challenge for the school system. Despite a proactive policy, many students with disabilities remain excluded. This is the case for the majority of children with inv dup del(8p) syndrome. In this research program, we will attempt to identify and understand the difficulties faced by these children and their parents in their schooling. To this end, two studies will be carried out. The first will involve interviews with parents of children with inv dup del(8p) syndrome and their teacher(s), to identify difficulties and possible levers. A second study will use a questionnaire with teachers to understand the effect of the combination of "genetic disease" and "rare disease" on their perceptions of schooling potential. Taken as a whole, these studies should make it possible to improve schooling for children with rare chromosomal diseases in general, and for children with inv dup del(8p) syndrome in particular.Humanities and social sciences 10
2023Christine PEYRONDijonFoundation For Rare DiseasesNewborn screening, SeDeN-p3French parents' acceptability of extending first-line neonatal screening with or without genetics: SeDeN-p3Recent changes to France's bioethics laws, coupled with advances in treatment and technology, have prompted the question of whether newborn screening (NBS) should be extended in France. The University Hospital Federation TRANSLAD, in collaboration with the Société Française de Dépistage Néonatal, has therefore created the SeDeN Project (for Séquençage Dépistage Néonatal). Its aim is to measure expectations and obstacles to the extension of neonatal screening in France. This includes information for parents (by whom, when, how to be informed about DNN), the type of diseases to be screened (accessibility to treatment or care, age of symptom revelation, etc.) and the techniques used (place of genetic tools in particular). To this end, the SeDeN Project is interviewing the various stakeholders in France: healthcare professionals, parents and decision-makers (public and influential groups).
The SeDeN-p3 study is the part of the SeDeN Project that focuses on parents' opinions. This part is entitled "Acceptability, by parents in France, of the extension of neonatal screening with or without genetic testing in 1st intention". It gathers parents' opinions in different situations: birth, infancy, whether the child has a disease or not, and so on. Indeed, parents are the first to decide whether or not to undergo DNN, since it is not mandatory in France. Depending on the outcome, they are also the 1st to be impacted on their life and that of their child. A study of their perceptions, expectations and motivations for choosing DNN is therefore essential before any new screening is actually implemented. As the extension of DNN is underway in France, the SeDeN-p3 study will provide the elements needed to ensure that it is, in the light of parents' expectations.
Humanities and social sciences 10
2023Elise RICADATParisOvercoming Cystic FibrosisSickle cell disease, MucosviscidosisPsychosocial challenges of new treatments for cystic fibrosis and sickle cell diseaseThe Institut La Personne en Médecine (ILPEM), with the support of CERMES 3 (UMR 8211), wishes to submit a research project on the psychosocial experience of patients who have received innovative and recent treatments for two rare diseases: allogeneic hematopoietic stem cells for adolescents and young adults with sickle cell disease, and CFTR modulators for adults with cystic fibrosis.
It takes place against a backdrop of major therapeutic innovations that have led to significant progress in the symptomatic expression of these two diseases, as well as to significant changes in therapeutic approach and outcome. Their effects on the individual, psychic and social experience of the disease are still largely undocumented due to their recent nature. A paradox common to both pathologies, although very different, emerges in particular: while they undeniably lead to a clear improvement in symptoms from a medical point of view, and even to a cure in the case of sickle cell disease, they seem to provoke increased psychic and identity-related malaise in some patients.
This 18-month exploratory project aims to gain a better understanding of the subjective experiences of patients and their families, as well as clinicians and healthcare professionals, in order to improve support and care.
Using a qualitative, inductive, participatory and interdisciplinary approach, our results aim to propose hypotheses to highlight the apparent paradox produced by the introduction of these new treatments; to produce general data on the psycho-social aspects of their effects; to identify whether these new treatments modify the caregiver/patient relationship. And ultimately, to create a multi-disciplinary and multi-professional dynamic to build more ambitious future projects concerning each of these two pathologies and ensure their participative feasibility in the longer term.
Humanities and social sciences 10
2023Nadine PRIOA-LELOUEYCaenFoundation For Rare DiseasesRare kidney diseases / Autosomal dominant polycystic kidney diseaseAssessment of anxiety at the first nephrology consultation in patients with polycystic kidney disease.Autosomal dominant polycystic kidney disease (ADPKD) is a rare disease affecting one in every 2,500 people in Europe. The 2015 survey of rare disease patients highlights the psychosocial impact of the disease. Due to its genetic nature, PKRAD patients most of the time have knowledge of Chronic Kidney Disease through the experiences of their loved ones. They therefore anxiously anticipate their future as a curse. Nephrology guidelines make care anxiety a priority area for research. Psychological research points to a feeling of guilt linked to the transmission of a genetic disease, and denial is the most common psychological defense in patients with hereditary nephropathy. In our practice, patients regularly report avoidance of the first specialist consultation, with deleterious consequences for disease progression. This first consultation in a specialist department is therefore a key stage in the management of the disease. The aim of this study is therefore to evaluate anxiety during this first consultation in patients with CKD, in comparison with those with polycystic fibrosis. In the medium term, it will enable us to improve the care of these patients by designing a dedicated reception system. This evaluation will be quantitative (anxiety measurement scales proposed to 390 MRC patients coming for their first nephrology consultation at Caen University Hospital). It will also be qualitative (face-to-face interview and analysis of the discourse and psychological protection mechanisms of 10 patients with polycystic kidney disease and 10 patients with other kidney diseases). The results should highlight a higher rate of anxiety at the first consultation in polycystic patients, and more extreme psychological protection mechanisms.Humanities and social sciences 10
2023Loïc GUILLOTParisAwards - Alnylam PharmaceuticalsCystic fibrosisPreclinical evaluation of a microRNA as an anti-inflammatory agent, promoting epithelial repair and limiting infection in cystic fibrosisCystic fibrosis is a rare genetic disease affecting some 80,000 patients worldwide. The disease begins at birth, and cystic fibrosis patients have a limited life expectancy, as their lungs deteriorate over the course of their lives. In particular, they are susceptible to repeated bacterial attacks, which progressively trigger a major inflammatory response and impair their ability to breathe normally. Bacterial resistance to antibiotics is a public health problem, requiring the development of new, innovative therapeutic molecules. In cystic fibrosis patients, we propose to use a molecule called microRNA, which has the ability to bind to the RNA of a target gene and inhibit its action. This strategy will both reduce inflammation in the lungs and prevent bacteria from damaging them.Alnylam Pharmaceuticals 2023 Award
2023Nicolas CENACToulouse Awards - APICIL FoundationChronic Pseudo Intestinal Obstruction (CPIO)Therapeutic value of metabolites derived from intestinal microbiota in visceral pain associated with chronic intestinal pseudo-obstruction (CIPO) in children
Pediatric Chronic Pseudo-Intestinal Obstruction (CPIO) is a rare condition characterized by the chronic inability of the gastrointestinal tract to propel its contents, leading to mechanical obstruction. Visceral pain severely impairs the quality of life of patients suffering from this potentially fatal condition. There is no curative or symptomatic solution for this syndrome. In an exploratory clinical study, eight POIC patients were treated with fecal microbiota transfer. Eight weeks later, symptoms of pain and bloating were reduced. This suggests a link between microbiota and POIC pain symptoms. The main aim of our project is to characterize the taxonomic and functional composition of the microbiota of pain patients with POIC, and to assess whether metabolites derived from this microbiota can regulate the activity of sensory neurons. In collaboration with the AP-HP Robert-Debré Center for Rare Digestive Diseases, we will select painful and non-painful POIC pediatric patients to build up a bio-collection of ileal effluents. We will establish the taxonomic and functional profile of the ileal microbiota and evaluate the effect of its metabolites on the activity of sensory neurons. This study should enable us to determine whether the microbiota could represent a therapeutic opportunity in visceral pain associated with POIC.APICIL 2023 Foundation Prize
2023Fabrice ANTIGNYParisFoundation For Rare DiseasesPulmonary rare diseases, Cardiovascular diseases / Pulmonary hypertension-Translational Research 2023
2023Juliane ISAACParisFoundation For Rare DiseasesRare head and neck malformations, Developmental anomalies and malformation syndromes / Oligodontia-Translational Research 2023
2023Fabrice ANTIGNYParisAFM TelethonRare lung diseases / Pulmonary hypertensionOrai1 Ca2+ channel: a new therapeutic target in PAHPulmonary arterial hypertension (PAH) is a rare and always fatal disease. PAH
is a major and growing economic and health burden worldwide, requiring the
development of new therapies, as current treatments are not curative. A
promising approach is to counter the adverse effects of deregulation of intracellular
intracellular calcium concentration. We have recently shown that increasing
expression and function of the Orai1 calcium channel in pulmonary arteries contributed to the
the pathogenesis of PAH. We have demonstrated that Orai1 could be a new therapeutic
to reduce PAH. Our aim is to treat PAH by repositioning an inhibitor of
PAH, an Orai1 inhibitor already used in several clinical trials. We will evaluate the
benefit of this drug candidate in different preclinical models of PAH.
We expect this project to validate the drug candidate through this repositioned Orai
inhibitor, so that clinical trials in PAH can be envisaged in the near future. The
proposal is supported by a strong rationale and a large amount of data generated in a
favorable environment (French reference center for pulmonary hypertension and
INSERM U999). We aim to validate the relevance of this Orai1 inhibitor as an innovative
to overcome the current limitations of PAH treatment options.
Proof of therapeutic concept 2023
2023Bénédicte CHAZAUDLyonAFM TelethonNeuromuscular disorders / Duchenne muscular dystrophyPromoting regenerative inflammation to improve muscle homeostasis in Duchenne Muscular DystrophyDegenerative myopathies are characterized by permanent damage to muscle tissue, chronic inflammation and fibrosis.
chronic inflammation and fibrosis. The latter are important pathological
in Duchenne muscular dystrophy (DMD), and represent obstacles to the efficacy
the efficacy of gene therapies aimed at correcting the genetic defect at the root of the pathology.
of the disease.
We have shown that, in contrast to the regeneration of healthy muscle, the resolution of
of inflammation is impaired in DMD muscles, with the presence of a pro-inflammatory
pro-inflammatory/profibrotic macrophages. Activation of the metabolic regulator AMPK
is beneficial in inducing resolution of inflammation by macrophages, leading to
improved muscle function in mice. This establishes the inflammatory
macrophage inflammatory change as a relevant therapeutic target in DMD.
However, effective molecules can be toxic. Our approach is to specifically target
macrophages to induce regenerative inflammation in the muscle.
regenerative inflammation in DMD muscle. Our results show that
encapsulated AMPK allosteric activators inhibit the properties of fibrotic macrophages in vitro
and in vivo in the DMD mouse model without adverse effects, establishing proof-of-concept
for their use.
The aim of the project is to optimize treatment and improve the efficacy of targeting
macrophage targeting.
Proof of therapeutic concept 2023
2023Gilles LAVERNYStarsbourgAFM TelethonAutosomal recessive infantile hypercalcemia, Idiopathic hypercalciuriaConsolidation of an innovative strategy for the treatment of calcitriol-mediated hypercalcemiaHigh levels of bioactive vitamin D (1,25D3 or calcitriol) cause hypercalcemia and,
associated with low parathyroid hormone levels, are the hallmark of a rare and refractory disorder
called calcitriol-mediated hypercalcemia (CMH). CMH has an impact on growth
growth and induce lethal renal dysfunction. Current treatments are based on
non-selective agents, with low efficacy and significant side-effects. It is therefore
urgent to develop new therapies.
The activities of 1,25D3 are relayed by its receptor VDR. We have recently identified
a VDR antagonist that normalizes its activity and serum calcium levels in mice
mice intoxicated with 1,25D3, without inducing side effects. This compound is therefore a
drug candidate for the treatment of MHC.
In this project, we aim to determine the activities and therapeutic window of this
VDR antagonist in Cyp24a1- and Slc34a1-null mice, two preclinical models of
MHC MODELS. The efficacy of this compound will be compared with that of fluconazole, a drug used outside the
in clinical use. In addition, its hepatic stability and pharmacokinetic parameters will be
parameters. At the same time, clinicians from the OSCAR and ORKID SMRFs will identify
CMH patients for clinical trials. The results obtained will provide important leverage
convince investors to pursue clinical development of this compound.
Proof of therapeutic concept 2023
2023Peter LENTINGParisAFM TelethonRare non-malignant haematological diseases / Hemophilia, congenital factor X deficiencyInducing albumin-mediated recycling of endogenous proteins: a novel strategy to treat quantitative deficiencies of plasma proteinsPatients with moderate or minor bleeding disorders are rarely eligible for prophylactic treatment, despite the idea that frequent minor bleeding has a major impact on their quality of life, both mentally and physically. This is particularly true for women and girls, who may experience heavy menstrual bleeding.
Our aim is to propose a new treatment strategy for these patients, characterized by a simple (subcutaneous) application on a weekly or fortnightly basis. In this context, we have developed a nanobody-based therapeutic platform that raises endogenous protein levels (which are reduced but not absent in these patients) by binding them to their own albumin. A proof-of-concept study has already been carried out, demonstrating that raising von Willebrand factor levels using this approach in a mouse model of type 1 von Willebrand disease corrects the bleeding tendency in these mice.
In this study, we will focus on rare coagulation disorders, in particular hemophilia A, hemophilia B and Stuart's disease/factor X deficiency.
Proof of therapeutic concept 2023
2023Laurent SCHAEFFERLyonAFM TelethonNeuromuscular disorders / Duchenne muscular dystrophyHDAC6 inhibitors to treat Duchenne Muscular DystrophyUnlike other histone deacetylases (HDACs), HDAC6 is strictly cytoplasmic and does not
deacetylates histones. Its substrates are cytoplasmic proteins such as α-tubulin.
We have recently shown that HDAC6 represses TGF-β signaling via deacetylation of
SMAD3. In vivo, we have shown that pharmacological inhibition of HDAC6 improves
the phenotype of the DMD mouse model (mdx) through a combined action that we have
of TGF-β signaling and microtubule stabilization.
microtubule stabilization. Selective HDAC6 inhibitors (HDAC6i) therefore offer additional advantages
advantages over pan-HDACi inhibitors (Osseni et al., 2022).
The mdx mouse models present a mild phenotype and partially recapitulate the trajectory
and severity of DMD in humans. Frédéric Relaix's laboratory has created a rat model of DMD
which faithfully reproduces the human pathology (Taglietti et al., 2022 & 2023). Before considering
clinical trials on DMD patients, we propose to test a promising
HDAC6i drug candidate in this highly relevant model.
In addition, the effect of HDAC6i will be tested on primary muscle cells from patients with
DMD patients in order to gain a first insight into their beneficial effects on human muscles.
Overall, this study will provide sufficient proof-of-concept to advance a selective
HDAC6i as a potential oral treatment for Duchenne muscular dystrophy.
Duchenne muscular dystrophy. The variability of the DMD rat genetic background and the use of
cells will enable us to approach this stage of translation to patients with a focus on precision medicine.
on precision medicine.
Proof of therapeutic concept 2023
2023Xavier DEZITTERLilleFoundation For Rare DiseasesPulmonary rare diseases / Idiopathic Pulmonary FibrosisPositive modulators of P2RX7 as a therapeutic strategy in Idiopathic Pulmonary FibrosisIdiopathic pulmonary fibrosis (IPF) is a rare (ORPHA:2032), chronic disease that progressively evolves into established fibrosis and respiratory failure. This devastating and incurable disease affects hundreds of thousands of people worldwide, underscoring the need for new therapeutic approaches.
We have demonstrated that a molecule that increases the activity of the P2X7 purinergic receptor, a so-called "positive modulator" of P2X7, can lead to remodeling of the immune compartment and improve fibrosis in a mouse model of fibrosis. This molecule establishes proof of concept for the use of P2X7 positive modulators in fibrosis. However, the positive modulators already described are few in number and not very active in vivo, which limits their therapeutic use. The aim of our project is to carry out a high-throughput screening of chemical libraries in order to identify potent P2RX7 positive modulators as drug candidates in pulmonary fibrosis. To this end, we have already developed a method for screening P2X7 modulators based on the measurement of P2X7's ability to bring calcium into cells. This method is based on fluorescence measurement, which can be carried out at high throughput. We would now like to carry out high-throughput screening of compounds using the "Ariadne-Criblage" screening platform, based at the Institut Pasteur in Lille. This platform has all the equipment needed to miniaturize and automate our test, as well as a bank of over 90,000 compounds selected for their chemical diversity and structural properties compatible with future drug development. Among these compounds, we will be testing the Prestwick chemical library, made up of drugs already on the market, in order to reposition an existing drug for pulmonary fibrosis.
Once P2R7-modulating compounds have been identified, our team has the knowledge and know-how to test and/or optimize these compounds, then test them in vivo, to rapidly demonstrate their potential as drug candidates in pulmonary fibrosis.
High throughput screening / Hit to lead 2023
2023Arnaud MONTEILMontpellierFoundation For Rare DiseasesRare neurological diseases / CLIFAHDD syndromeDiscovering new therapies for patients with the CLIFAHDD syndrome, a sodium leak channel NALCN-Related DiseaseCLIFAHDD syndrome (for "Congenital contractures of the Limbs and FAce, Hypotonia, and
Developmental Delay") is a genetic disease classified as ultra-rare which, to date, affects
fifty children worldwide. Nevertheless, new cases are regularly
described on a regular basis. The disease begins at birth and is characterized by a wide range of symptoms
symptoms of varying severity, including developmental delays, apnea and motor problems
apnea and motor problems, distal arthrogryposis and premature death. CLIFAHDD syndrome
syndrome results from mutations in the NALCN gene. The NALCN channel protein is a key player in the proper
several cell types in the body, including neurons and endocrine cells.
endocrine cells. We now know that the mutations that induce CLIFAHDD syndrome are mutations that
mutations that render NALCN too active. In this context, drugs likely to specifically reduce
activity of NALCN represent promising therapeutic avenues for a disease for which there is no
pathology for which no treatment currently exists. Against this background, this project brings together a
team of researchers specialized in the study of NALCN and a technological platform, the
ARPEGE platform, whose expertise in molecule screening is internationally recognized. L'
objective is to develop and implement a method for identifying molecules that inhibit
NALCN function, using a high-throughput automated screening system. L'
identification and validation of such molecules will enable us to propose new
therapeutic approaches for patients suffering from CLIFAHDD syndrome.
High throughput screening / Hit to lead 2023
2023Aline GHINETLilleFoundation For Rare DiseasesRare neurological diseases / Creutzfeldt-Jakob disease (CJD), Fatal familial insomnia (FFI), Gerstmann-Sträussler-Scheinker syndrome (GSS syndrome)Structural optimization of pre-identified hits to obtain novel first-in-class anti-prion compoundsCreutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia are rare neurodegenerative diseases known as spongiform encephalopathies. Creutzfeldt-Jakob disease (CJD) affects one person per million population per year, or 100 to 150 cases per year in France. The first symptoms of CJD are often non-specific, such as depression or anxiety. This is followed by problems with memory, orientation and language. This dementing syndrome is progressively associated with involuntary muscle spasms, disturbances of balance or vision, tremors and epileptic seizures. CJD is the only human disease that can be either sporadic (80%), genetic (15%) or acquired through contamination (<5%). Les cas sporadiques apparaissent en moyenne vers l'âge de 60 à 65 ans. Le syndrome de Gerstmann–Sträussler–Scheinker touche entre 1 à 10 personnes pour 100 000 000. Ce syndrome est d’origine génétique. L'insomnie familiale, qui a une prévalence <1 > During the recent in vitro screening of our 3,000-molecule JUNIA-HEI chemical library, carried out by Dr. Cécile Voisset's team at the University of Brest, on S. cerevisiae prions [PSI+] and [URE3], molecules with sufficient activity to be considered hits were identified. The most promising hits, positive against the yeast prions [PSI+] and [URE3], were then tested against the mammalian prion PrPSc in a cell-based assay. Our aim is to optimize the activity of the most promising compounds identified by performing chemical modulations on the skeleton of pre-identified hits. These structural modifications will enhance affinity against the mammalian prion PrPSc, optimize solubility of the newly synthesized congeners, improve pharmacokinetic parameters and generate structure-activity relationships (SARs). This will result in an optimized lead compound, a candidate for preclinical testing as a potential anti-prion drug.
This research program will make it possible to identify new anti-prion compounds and thus new therapeutic avenues for patients suffering from prion diseases for which no therapeutic solution is currently available.
High throughput screening / Hit to lead 2023
2023Sandrine GULBERTINancyFoundation For Rare DiseasesMucopolysaccharidosesTowards the hit to lead stage in a new substrate reduction therapy strategy in mucopolysaccharidoses targeting the 4GalT7 glycosyltransferaseMucopolysaccharidoses are rare genetic diseases caused by a defect in the degradation of large sugar molecules called mucopolysaccharides or glycosaminoglycans. As these molecules are not degraded, they accumulate in tissues, causing severe damage to organs, notably the brain, and reducing the quality and length of life of patients. Various types of treatment have been proposed for certain forms of the disease, but their complexity and cost mean that their efficacy remains insufficient to provide lasting relief.
The overall aim of the project is to develop compounds that could lead to more effective treatments, in particular by improving the most severe symptoms of the disease, such as those affecting the nervous system. We are looking for small-scale compounds that would specifically block a step in the synthesis of molecules that accumulate in tissues, in order to reduce their deleterious effects. To this end, we have chosen as our target one of the players involved in the early stages of the synthesis process of these molecules in tissues. In the first stage of the project, we tested over a thousand chemical compounds for their ability to block the targeted synthesis pathway, and selected around ten candidate molecules. The activity of these candidate compounds was confirmed in a second series of tests, enabling us to select five molecules which are currently being tested in human cells. In this project, the identification of active molecules will enable us to identify chemical families to target and optimize their structure to obtain even more effective molecules through complementary approaches using medicinal chemistry and molecular modeling. The two to three most active molecules will serve as a basis for proposing new chemical structures. After a feasibility study, these molecules will be chemically synthesized and tested for their biological activity using models available from our partners. The best candidate molecules resulting from these tests will be validated on our target and in human cells, before finally being tested on patient cells, with the longer-term prospect of clinical trials if successful. We hope that this project will provide a new avenue of treatment for the various forms of mucopolysaccharidosis, including the most severe forms involving the nervous system.
High throughput screening / Hit to lead 2023
2023Alexis OSSENILyonFoundation For Rare DiseasesNeuromuscular disorders / Duchenne muscular dystrophyDesign and development of new HDAC6 inhibitors to treat Duchenne Muscular DystrophyDuchenne muscular dystrophy (DMD) is the most common and fatal form of muscular dystrophy. It is a devastating and fatal X-linked progressive degenerative muscle disease affecting around 1 in 3,500 boys. This myopathy is characterized by a mutation in the gene coding for dystrophin. Duchenne patient muscles are characterized by continuous cycles of degeneration and regeneration, and this pathological process is accompanied by inflammation and fibrosis, which contribute to fatal muscle wasting and loss of function of skeletal muscles and the heart. Despite detailed characterization of the pathogenesis of this myopathy and considerable research efforts, no cure is yet available for Duchenne myopathy patients. Gene-based therapeutic strategies, such as exon skipping, stop codon deletion, adeno-associated virus (AAV) delivery of mini or micro-dystrophin or CRISPR/Cas9 gene editing, are being actively studied to treat this myopathy. Nevertheless, glucocorticoids remain the reference treatment, acting primarily as anti-inflammatory drugs. However, in recent years, a large number of pharmacological treatments have been explored and developed to improve the quality of life of patients with this myopathy.
Over the past decade, an enzyme called HDAC6 has attracted considerable interest as a potential therapeutic target for several neuromuscular diseases. Pharmacological inhibition of this enzyme markedly improves the phenotype of mouse models of DMD by reducing muscle atrophy, reducing fibrosis, increasing protein synthesis, and restoring neuromuscular junctions. However, no HDAC6 inhibitor is currently available on the drug market.
Our aim is to identify, design and develop new selective, orally bioavailable HDAC6 inhibitors, based on the best HDAC6 inhibitor known to date: tubastatin A. This inhibitor is composed of three domains, and our strategy is based on modifying these 3 domains to identify non-proprietary compounds. The results of this study will therefore prove essential in paving the way for the development of a completely new class of selective HDAC6 inhibitors for human use, which do not have the disadvantages of the older classes of HDAC inhibitors developed to date. We plan to propose strong candidates for entry into regulatory studies with a view to eventually initiating human clinical trials.
High throughput screening / Hit to lead 2023
2023Damien OUDIN DOGLIONIGrenobleNovo NordiskSickle cell diseaseAdaptation and evaluation of the feasibility of the FACETS fatigue management program in adult patients with sickle cell disease.Sickle cell disease is the most common genetic disorder in the world. While pain is the most obvious
of the disease, fatigue is also a very common symptom. It is the second
most reported symptom (93.6%) after pain, with 75% of respondents reporting significant fatigue.
fatigue. Fatigue can be explained by several factors: disease-specific factors (eg.
(e.g. severity, worsening over time, hospitalization), personal factors (e.g. age, gender) and psychological factors.
psychological factors. The way in which people react to fatigue at cognitive, emotional and behavioural levels plays a role,
behavioral response to fatigue plays an important role in its perpetuation or worsening. Moreover
fatigue is complicated to treat, given its multifactorial nature. However, French recommendations
recommendations for the management of sickle cell disease do not offer any support. This finding is
surprising, given the existence of fatigue management programs for other chronic diseases, such as the
such as the FACETS program validated for people living with multiple sclerosis. In
this study, we aim to adapt this program to adults with sickle cell disease, and to verify its feasibility in this population.
feasibility in this population.
Novo Nordisk Award 2023
2023Régis GIETRennesFondation Les Ailes / Groupama Loire BretagneEpileptic and developmental encephalopathies (EED)Functional study of TACC1, a new gene involved in a rare form of developmental epileptic encephalopathyEpileptic and developmental encephalopathies (EED) are a group of severe childhood epilepsies. These diseases are characterized by abnormal brain development associated with frequent epileptic seizures. The identification of a new gene responsible for EED therefore represents a major step forward, enabling us to better understand the cellular mechanisms that cause the disease, inform families about the risk of recurrence, and ultimately consider participation in clinical trials. An international collaboration has led to the discovery of a new gene involved in EED in an American family and a French family from the Grand Ouest region, whose affected children have EED resistant to the therapies usually used. We propose to examine the role of this new gene using cellular approaches coupled with high-resolution microscopy. These studies will enable us to gain a better understanding of the deficient cellular mechanisms in these two patient families and, in the longer term, to envisage alternative therapeutic approaches.Outside AAP
2023Fabrice LEJEUNELilleROTARY LinselleCystic fibrosisCombinatorial therapeutic approach for more effective correction of certain mutations in cystic fibrosisThe aim of the project will be to evaluate the efficacy of combinations of NMD-inhibiting molecules and transcriptase-activating molecules in correcting nonsense mutations in cystic fibrosis.Outside AAP
2023Agnès DUMAS / Hélène MELLERIOParisFoundation For Rare DiseasesTransition platforms: Understanding the expectations of parents of young rare disease carriersOutside AAP
2023Catherine BUINancyRoquetteEhlers Danhlos syndromeUnderstanding to Cure: Functional exploration of β1,3 galactosyltransferase 6 (B3GALT6) deficiency in a rare genetic connective tissue diseaseThe aim of the present project is to gain a better understanding of the pathogenesis of a rare form of SED using a global, multidisciplinary approach, and to highlight the different biological pathways or cellular mechanisms affected by these mutations, which could be targets for future treatments.

To this end, we propose to:
(A) To analyze and compare the transcriptomic profiles of our three-dimensional cell model (2) (eukaryotic cells invalidated for the B3GALT6 gene versus control cells) by RNA-sequencing.
(B) Establish and compare the proteomic profiles of our three-dimensional cellular model (eukaryotic cells invalidated for the B3GALT6 gene versus control cells) by mass spectrometry.
(C) To validate the "omics" data generated in (1) and (2) by biochemical and functional studies, and to carry out an integrative analysis of these data to identify new molecular players and biological pathways involved in the pathogenesis of this rare form of EDS.

Taken together, this knowledge will provide a global view of the consequences of 3GalT6 deficiency, and identify the metabolic pathways and cellular mechanisms altered as a result. This work is necessary to better understand patient symptomatology, and in the longer term will enable us to propose new therapeutic avenues with a view to personalized medicine.
Outside AAP
2024Carolina BAEZA-VELASCOParisFoundation For Rare DiseasesVascular Ehlers-Danlos, Marfan and Loeys-DietzAdjustment to illness and psychosocial needs of people with hereditary aorthopathies: a mixed-methods study (APSAOR)Introduction: Vascular Ehlers-Danlos syndrome (vEDS), Marfan syndrome (MS) and Loeys-Dietz syndrome (LDS) are rare genetic disorders in which connective tissue damage leads to severe vascular complications, including aortic aneurysms and dissections. These potential arterial events lead to an increased risk of premature death. Studies describing patients with these hereditary aortopathies (HA) from a psychosocial perspective are almost non-existent. Consequently, the impact of the disease on patients' daily lives and their psychosocial needs remain poorly understood.
Aims: This cross-sectional observational study with mixed methodology (quantitative and qualitative) aims to: 1) explore the psychosocial adjustment to illness of people with HA (SEDv, SLD and SM) and compare it according to pathology. 2) to explore the sociodemographic, clinical and psychosocial factors associated with adjustment to illness, and 3) to explore, via a semi-structured interview, the subjective experience and meaning given to illness, as well as the perceived psychosocial needs of people with these HAs.
Method: People aged 18 and over with a molecular diagnosis of SEDv, SLD and SM will be included. In the first part of the study (quantitative component), participants will complete a series of online self-questionnaires assessing adjustment to illness, quality of life, anxiety-depressive symptomatology, coping strategies and illness representations. In a second phase, they will complete a structured interview assessing mental disorders. For the qualitative component, a sub-group of patients will be selected according to pathology (between 8 and 12 per pathology) and availability for a more in-depth interview lasting around 40 min. This sub-group will be assessed with a semi-directive interview consisting of a series of open-ended questions to explore patients' illness experience and psychosocial needs.
Expected results: Fill a gap in the literature concerning adjustment in people with HA. Identify new therapeutic targets for a psychologically understudied population, and sensitize the medical community to the need to consider psychosocial aspects in the overall management of patients in order to minimize their potential vulnerabilities.
Humanities and social sciences 11
2024Hélène KANERouenFoundation For Rare DiseasesSickle cell diseaseGrowing up and building your future with sickle cell disease (GrandCAD)A rare genetic disease, sickle-cell anemia constrains participation in social, school, recreational and sporting activities in a multitude of ways. Within the framework of an anthropology that considers children as social actors with their own reasons for acting and developing personal strategies, we propose to study how children and adolescents suffering from sickle-cell anemia construct their social lives, their identities and their plans for the future. The aim is to question how they negotiate their postures to "grow up" between constraints linked to the management of their illness and expectations linked to the social constructions of age. This research is structured around four lines of inquiry: (1) adaptations to illness and treatment, (2) family relationships affected by illness, (3) activities and relationships with others, (4) perceptions of the future and plans. A case study methodology will be used, combining observations and interviews with around twenty children and adolescents and their parents. These investigations will enable a biographical approach to be deployed, putting into perspective the evolution of the pathology, care trajectories and bodily and social experiences; and will help identify the stages requiring readaptation. The specificity of sickle-cell anemia leads us to address situations where the experience of a rare disease is shaped by contexts of migration, mobility and transnational relations. This work will enable us to identify and valorize the solutions and adjustments found by young people in the face of the multiple difficulties they encounter, and through this research process to contribute to improvements in the support and care offered by health services and associations. (GrandCAD)Humanities and social sciences 11
2024Johanna CALDERONMontpellierFoundation For Rare DiseasesCongenital heart diseaseDecision-making and risk behaviours in rare congenital heart disease: QUALINEURO-REHAB Risk ancillary pilot studyComplex congenital heart disease (CHD) requiring open-heart surgery accounts for around ¼ of all CHDs, and is one of the rare diseases listed on ORPHANET, such as tetralogy of Fallot, d-transposition of the great vessels, or univentricular heart. Developmental and mental health disorders, particularly in relation to executive functions and emotional regulation, are the most widespread, and arguably the most disabling, long-term morbidity in the population living with complex CC. The negative repercussions are family, school and social. Crucially, problems with emotional regulation and decision-making may also increase their cardiovascular health risk. To date, no study has explored the psychological decision-making processes in CC and their influence on health risk behaviors in these rare diseases. Yet it is crucial to understand the underlying cognitive and psychopathological mechanisms.
QUALINEURO-REHAB Risk is a pilot study ancillary to the QUALINEURO-REHAB (QNR) randomized controlled trial, and aims to 1/ characterize the decision-making abilities and risk behaviors of adolescents and young adults aged 13 to 25 with complex CC by means of direct quantitative and qualitative assessment, 2/ identify the psychological profiles, at executive level (i.e., working memory, cognitive flexibility) and emotional (i.e., anxiety levels, emotion regulation) profiles associated with decision-making abilities and risk-taking behaviours, and 3/ assess the impact of the intervention proposed in our randomized controlled QNR trial on decision-making and health risk-taking processes in this group.
Indeed, a better understanding of the psychological processes at the root of health risk behaviours could considerably impact the development of prevention recommendations, vital in the care of young people with complex heart defects. If the results of the interventional study are positive, they would have major public health implications for the organization and management of young people with heart defects.
Humanities and social sciences 11
2024Catherine GOUEDARDParisFoundation For Rare DiseasesWillebrand's diseaseDeveloping the ability to act on work and health pathways with Willebrand disease patients and their carers (DevCAP-Willebrand)The aim of the research is to document the experiences of people affected by Willebrand's disease in relation to their career path, and more specifically the work they undertake to maintain their health. This is an unexplored area in the scientific literature, even though it raises crucial social issues from the point of view of patient associations. The aim is to shed light on how these people cope with episodes of vulnerability in the workplace, in relation to their illness, so as to remain the authors of their professional future, and rebuild the power to act despite the ordeals. This work of maintaining health relies on external resources, offered by the environment, and internal resources, in particular experiential knowledge, which is often implicit. The originality of the method lies in a support approach conceived from a developmental ergonomics perspective. Implemented with some fifteen participants, this method invites them to retrace their career path, to represent it using a mediating and innovative reflexivity tool (the chronicle of vulnerability) and to explain the significant moments and resources mobilized/created. Working with the researcher, this process of biographizing and clarifying lived experience is an opportunity to raise awareness, create meaning and develop the ability to act. Setting up focus groups with participants is a further opportunity to work on experience, and to develop peer recognition of resources and experiential knowledge useful to the community of sufferers. For those who support them, whether in a medical, professional or associative context, the analysis of the complexity of these experiences, carried out in collaboration with the researchers, will enable us to identify levers to support development processes for the people concerned. Together with our partners, the results will help to identify ways of creating a new support system within the care pathway, in line with the professional transitions and bifurcations experienced by the people concerned. By developing caregivers' ability to take action, the approach aims to promote empowering care pathways to articulate work and health issues, transferable to other rare disease support contexts.Humanities and social sciences 11