Abstract
Mutations within over 250 known genes are associated with inherited retinal degeneration. Clinical success following gene-replacement therapy for congenital blindness due to RPE65 mutations establishes a platform for the development of downstream treatments targeting other forms of inherited ocular disease. Unfortunately, several challenges relevant to complex disease pathology and limitations of current gene-transfer technologies impede the development of related strategies for each specific form of inherited retinal degeneration. Here, we describe a gene-augmentation strategy that delays retinal degeneration by stimulating features of anabolic metabolism necessary for survival and structural maintenance of photoreceptors. We targeted two critical points of regulation in the canonical insulin/AKT/mammalian target of rapamycin (mTOR) pathway with AAV-mediated gene augmentation in a mouse model of retinitis pigmentosa. AAV vectors expressing the serine/threonine kinase, AKT3, promote dramatic preservation of photoreceptor numbers, structure, and partial visual function. This protective effect was associated with successful reprogramming of photoreceptor metabolism toward pathways associated with cell growth and survival. Collectively, these findings underscore the importance of AKT activity and downstream pathways associated with anabolic metabolism in photoreceptor survival and maintenance.