Project Summary Retinitis Pigmentosa (RP) is an inherited retinal disease afflicting 1 in 4,000 people worldwide. The disease progresses initially by rod photoreceptor degeneration caused by mutations in rod-specific genes, although different mutations in different genes converge upon the same rod degeneration phenotype in this disease. However, it is the subsequent cone photoreceptor degeneration that causes loss in daylight color vision and, ultimately, diminishing quality of life for most patients. While gene therapy to replace a mutated gene with a functional copy has been successful, given the heterogeneity of mutations and genes, treating all RP cases by targeting the rods is difficult. Instead, a generic therapy to preserve the cones upon rod degeneration may lead to a more comprehensive therapeutic option. Previously, we discovered that activation of the Retinoic Acid signaling pathway is sufficient to promote cone survival in a mouse model of RP. To further develop this signaling pathway as a potential gene-agnostic therapeutic for all patients with RP, we will develop a novel AAV-based Retinoic Acid signaling activator to test whether it can improve photopic visual acuity in multiple mouse models of RP. Furthermore, using this signaling pathway as a molecular handle, we will aim to elucidate the molecular and cellular mechanisms downstream of this signaling pathway that contribute to the cone survival effect.