Thanks to support from the VHL Association and the Rare Diseases Foundation, a research group at the Thorax Institute has succeeded in creating the very first cellular model of von Hippel-Lindau disease, paving the way for new treatment options for patients.
The team is studying the von Hippel-Lindau (VHL) gene and the inherited disorders associated with mutations in it. Depending on the specific mutations, patients develop polycythemia (overproduction of red blood cells) or von Hippel-Lindau (VHL) disease, which is characterized by the development of highly vascularized tumors in many organs: hemangioblastomas of the central nervous system and the retina, renal cell carcinomas, pheochromocytomas, or neuroendocrine tumors of the pancreas. Although this gene has been studied for decades, it is still not understood why patients develop such different conditions and, in the case of VHL disease, why—even though all of the patients’ cells carry the same inherited mutation—tumors develop only in certain specific organs?
An original hypothesis: the neural crest
To answer this question, the research team hypothesized that all manifestations of the disease share a common cellular origin: neural crest cells. These cells produce erythropoietin, the hormone responsible for red blood cell production. Furthermore, during embryonic development, these cells migrate along the spinal cord and specifically colonize the organs where VHL tumors arise—the retina, inner ear, central nervous system, kidneys, adrenal glands, and pancreas. This line of inquiry could finally explain why hemangioblastomas so often appear along the spinal cord.
A Technical Feat: Reprogramming Patients' Cells
To test this hypothesis, the team used an innovative method: reprogramming blood cells from VHL patients into induced pluripotent stem cells (iPS cells), then differentiating them into neural crest cells and endothelial cells—the two cell types directly involved in the formation of hemangioblastomas.
This work led to a major breakthrough: the creation of the first cellular model of von Hippel-Lindau disease, a model that did not previously exist anywhere in the world. Thanks to this model, the team can now study the properties of these cells as well as the impact of the factors they secrete on the formation of the blood vessels that give rise to hemangioblastomas.
Results Already Shared with the Scientific Community
This groundbreaking model has been presented at numerous national and international conferences, in the form of invited talks and poster presentations. It has also helped advance other research on the VHL gene and the hypoxia pathway, leading to the completion of several scientific publications that are currently in preparation. In each of these presentations, the Rare Diseases Foundation and the VHL France association were acknowledged and warmly thanked for their indispensable support.
Toward New Biomarkers and Therapeutic Targets
Work is currently underway to further develop this cellular model. Ultimately, it could lead to the identification of new biomarkers and therapeutic targets for patients with VHL disease, as well as shed light on other unresolved questions, such as the link between certain mutations in the VHL gene and the development of polycythemia.
This major scientific breakthrough would not have been possible without the commitment of patients, families, and donors who, through the VHL Association, make this type of basic research on rare diseases possible.
" A huge thank you to the VHL Association and the Rare Diseases Foundation for their invaluable support of this project."
– Betty Gardie, Director of Studies at the EPHE, Research Unit at the Institute of Thoracic Medicine, Nantes.