Early-onset retinal degenerations

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DESCRIPTION (provided by applicant): Early-onset retinal degenerative diseases, including those termed Leber congenital amaurosis, are a severe form of blindness without treatment. Mutations in the retinal pigment epithelium (RPE) gene encoding RPE65 are one of the few known molecular causes of these blinding diseases. The objective of this application is to investigate a potential oral therapy in animal models of RPE65-associated human retinal degeneration and determine the candidacy of patients with the molecularly comparable retinal disease. There is the advantage that both a genetically engineered murine "small animal" model and a naturally occurring canine "large animal" model are available. In preliminary studies, retinoid flow and retinal physiology in Rpe65-deficient mice were analyzed and there was no rod photo pigment and severely impaired rod physiology. There is a distinct disease phenotype with photoreceptor function severely abnormal at a time when morphology is nearly normal. Slow degeneration of photoreceptors and RPE causes a convergence of structural and functional damage at later disease stages. Using an orally-administered cis-retinoid, an attempt was made to bypass the biochemical blockade in the visual (retinoid) cycle caused by the genetic abnormality. Within 48 hours, there was formation of rod photopigment and dramatic improvement in rod physiology. The specific aims of the current multi-disciplinary application lead directly from these encouraging results: (1) determine in Rpe65-deficient mice the short- and long-term consequences of oral cis-retinoids; (2) study the RPE65-mutant canine model for disease mechanism and response to oral cis-retinoids; and (3) define the disease expression in humans with early-onset retinal degenerations due to RPE65 mutations, specifically inquiring whether, like the models, there is a detectable phase when photoreceptor function is nearly absent but retinal structure remains, and thereby an opportunity for effective intervention independent of strategy. This application provides a route map that hopefully will be well-traveled in the future as we seek to restore vision in currently incurable genetic retinal degenerations from identification of molecular cause in human blindness, to experimentation and trials of mechanism-based intervention in small and large animal models, and then a circling back to the afflicted humans to clarify relevance to them and their candidacy for specific treatments, with the long-term goal of safe and efficacious clinical trials.