Grant: Project Grant

Our goal is to identify therapies for a group of genetic diseases, the Peroxisome Biogenesis Disorders (PBD). Progressive retinal degeneration leading to blindness is one of the major, untreatable handicaps in this condition and correcting vision would vastly improve the quality of life of these individuals. PBD are due to mutations in PEX genes, whose protein products are required to assemble peroxisomes- intracellular organelles vital for complex fat metabolism. Most persons with PBD have a common mutation in the PEX1 gene, that encodes a misfolded protein, PEX1-G843D, with significant residual function. These children and adults have a condition characterized by progressive tissue damage due to ongoing peroxisome dysfunction over time. Importantly, there is a window of opportunity to intervene and halt this progression. We have now identified two promising drugs (approved for other purposes) that recover peroxisome function in patient cell lines by acting as 'chaperones' to improve PEX1-G843D function. We also have a mouse model with the equivalent mutation that has a retinal degeneration similar to patients. A recent pilot study showed that our candidate drugs recovered retinal functions in the mice by electroretinogram studies. In this project, we will study the murine retinal disease to determine the best time points to intervene for therapy and accurate clinical endpoints to measure response. Expanding our patient cohort, we will also carefully study and compare the human retinal disease to ensure we can translate this therapy to patients. If successful, this will be the first targeted therapy for PBD and address a devastating feature, blindness. The information we gather on the course and pathophysiology of the disease, will also enable and accelerate all future, independent avenues for correction of the retinal disease in PBD. Finally, we expect that these chaperone drugs will also be able to treat other body systems involved in this disease.