Summary Of the retinal degenerative diseases that affect 9 million Americans, rod and cone photoreceptor dystrophies are arguably the most devastating. Gene therapy is a potential means to strengthen photoreceptor viability. However, the first human gene therapy trial for retinal degeneration found improved visual function but did not slow degeneration of photoreceptors. The goal of this gene therapy-oriented proposal is to determine whether therapy is achievable in the context of an already diseased retina and at what timepoints gene therapy should be administered in order to improve functional vision in rod and cone dystrophies. We will determine whether cone-specific rescue is possible at late stages of disease. Finally, we will determine the latest timepoint at which gene therapy can be administered for rod monochromatism. To do this, we will use a novel, inducible genetic rescue system in the cone-specific G-protein, guanine nucleotide binding α-transducin 2 (Gnat2), which will allow us to conditionally reverse GNAT2-deficiency while controlling the temporal and spatial aspects of phenotypic reversal. We will also use a phosphodiesterase 6 (Pde6b) mouse as a model for rod dystrophy. The Gnat2floxSTOP/Gnat2floxSTOP::Arr3CreERT2/WT and Pde6cfloxSTOP/Pde6cfloxSTOP::Arr3CreERT2/WT programmable models will provide a platform for contributing to ongoing efforts aimed at increasing restoration of visual function following gene therapy for rod- and cone-mediated dystrophies. They will also allow us to address several compelling, clinically relevant questions: Is the brain’s circuitry sufficiently plastic to recover from the pathological changes caused by the Gnat2 mutation? Is there a point of no return after which, despite reversion of the genotype to wild type, cones cannot be salvaged? Can temporal barriers to gene therapy be relieved by metabolic reprogramming? Taken together, this proposal is certain to: i) determine whether metabolic reprogramming can serve as an efficacious, non-gene-specific strategy for treating retinal degeneration, ii) define the factors limiting interventional therapy, and iii) validate a new, inducible models of cone-mediated retinal degeneration.