Disease Mechanisms in Best Disease



 DESCRIPTION (provided by applicant): Best disease, or vitelliform macular dystrophy, is a human macular degenerative disorder characterized by progressive and irreversible central vision loss. The disease is caused by a host of different (largely missense) mutations in the gene BEST1. Currently there is no treatment or cure for this condition. In this multicenter, multi-PI proposal, we will evaluate the pathophysiology of Best disease using RPE cells derived from induced pluripotent stem cells (iPSCs) from patients with known BEST1 mutations. Preliminary data show that these cells recapitulate at least some the phenotypes of human RPE cells with Best disease. We propose multidisciplinary experiments that will lead to a better understanding of this blinding disease, and that include: determining the pathology of Best disease patient-derived RPE cell chloride conductance and cellular electrophysiology; determining the pathological relationship between different mutations, and between dominant and recessive forms of Best disease; and evaluating gene therapy/genome editing as a potential treatment for Best disease. These important studies will pave the way for new treatments for this disorder.