Mutations within over 250 known genes are associated with inherited retinal degeneration. Clinical success following gene replacement therapy for Leber’s congenital amaurosis type 2 establishes a platform for the development of downstream treatments targeting other forms of inherited and acquired ocular disease. Unfortunately, several challenges relevant to complex disease pathology and limitations of current gene transfer technologies impede the development of gene replacement for each specific form of retinal degeneration. Here we describe gene augmentation strategies mediated by recombinant AAV vectors that impede retinal degeneration in pre-clinical models of acquired and inherited vision loss. We demonstrate distinct neuroprotective effects upon retinal ganglion cell survival and function in experimental optic neuritis following AAV-mediated gene augmentation. Gene transfer of the antioxidant transcription factor, NRF2, improves RGC survival while overexpression of the pro-survival and anti-inflammatory protein, SIRT1, promotes preservation of visual function. In the context of inherited retinal disease, we show stimulation of anabolic metabolism following AKT3 gene transfer preserves photoreceptor viability and delays functional loss in a mouse model of retinitis pigmentosa. In addition to these neuroprotective strategies, we also describe an approach to improve the in vitro potency of AAV vectors that are restricted by tissue-specific regulatory elements. This strategy utilizes genome engineering based on CRISPR/Cas9 gene activation to reprogram cell lines to specifically and potently express tissue-specific promoters of interest from AAV vectors.