Molecular Pathophysiology of Von Hippel Lindau (VHL) disease

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ABSTRACT Von Hippel Lindau (VHL) disease is an autosomal dominant condition caused by mutations in the VHL gene, which normally functions to help target hypoxia-inducible factors for degradation when not required. Dominant VHL mutations have been reported to result in excessive production of pro-angiogenic factors, predisposing patients to development of a number of tumors including retinal capillary angiomas. Among the many challenges in studying and managing patients with VHL is the extensive phenotypic variability. For instance, family members that share the same disease causing mutation can display significant variability in their retinal disease phenotype. These clinical observations suggest that there are genetic modifiers that influence the severity of the patient’s retinal disease. Our center has strong research expertise in inherited retinal diseases, and we have performed extensive work with induced pluripotent stem cells (iPSCs) and CRISPR based genome editing for both the study of disease pathophysiology and development of novel gene based therapeutics. In this proposal we will use patient-derived iPSCs to generate retinal vascular cells for the study of VHL pathophysiology. By evaluating the transcriptome of retinal vascular cells generated from patients within the same family who have the same disease genotype but very different disease phenotypes, we hypothesize that we will be able to identify novel molecular regulators of retinal vascular tumor formation. Identification of such disease modifiers would provide us with both new prognostic indicators of disease severity and new targets for drug and gene-based treatments.