Therapies for defective photoreceptor outer segment development in blinding diseases

PROJECT SUMMARY/ABSTRACT The long-term goal of our research is to identify and develop therapies for defects in protein networks that are essential for the morphogenesis of photoreceptor outer segments (POS). These segments are a key compartment in photoreceptor neurons where the primary components of phototransduction reside, and their abnormal development or loss leads to blindness. This proposal specifically aims to investigate the importance of Prominin-1 (PROM1), a protein implicated in the development of POS. Multiple mutations in PROM1 are associated with a wide array of ocular defects, leading to vision loss. Animal models show the importance of Prom1 with POS dysmorphogenesis and progressive vision loss. Currently, there are no treatments for PROM1- associated blindness. Although both mouse models and human disease associations have demonstrated the importance of PROM1 in vision, the mechanisms underlying PROM1's role in disc morphogenesis and photoreceptor health remain unknown. Therefore, with two specific aims, this proposal will focus on 1) identifying an optimal therapeutic regimen for this disease and 2) uncovering the mechanisms by which PROM1 contributes to outer segment morphogenesis. To thoroughly address these objectives, we will employ a combination of AAV- mediated gene therapy in unique animal models that mimic the disease phenotype alongside electrophysiological measurements and biochemical analyses, including immunoprecipitation followed by proteomics. Our proposed studies align with Emphasis Area #1 of the NEI's recent strategic plan: "From Genes to Disease Mechanisms—Identification of ocular disease genes be leveraged to develop new strategies, models, and tools for elucidating genetic and environmental interactions at the cellular and systems level, and thereby accelerate mechanistic understanding and therapy development." The proposed research holds significant clinical potential, potentially leading to therapies for PROM1 mutations and, more broadly, for blindness resulting from defective outer segment development.