Several lines of evidence suggest that oxidative damage plays a role in the pathogenesis of age-related macular degeneration (AMD). We hypothesize that oxidative damage also plays an important role in cone cell death in retinitis pigmentosa (RP). If this is true, increased expression of antioxidant enzymes in photoreceptors may be a good therapeutic strategy in both disease processes. In this proposal, we plan to explore the role of the 3 isoforms of superoxide dismutase (SOD) in the oxidative defense system of photoreceptors. To assess the role of endogenous SODs, the effect of deficiency of SOD1 or 3 on photoreceptor survival will be tested in two models of oxidative damage, hyperoxia- and paraquat-induced retinal degeneration. The same two models, along with transgenic and self-complementary adeno- associated viral vector (scAAV)-mediated gene transfer approaches, will be used to test the hypothesis that increased expression of SOD 1, 2, or 3 protects photoreceptors from oxidative damage. The hypothesis that oxidative damage contributes to cone cell death in RP will be tested by determining if increased expression of SOD 1, 2, or 3 reduces cone cell death in two mouse models of RP. The data from all of these experiments in mice will help us to select the appropriate transgene(s) for definitive experiments in a transgenic pig model of RP. In those experiments scAAV-mediated gene transfer of an SOD or combination of SODs will be tested against null vector to determine if increased production of SOD(s) reduces cone cell death. The effects of SOD(s) alone will also be compared to co-expression of SOD(s) with brain-derived neurotrophic factor (BDNF) to determine if the co-expression approach provides additive benefit for cone survival. The major goal of this work is to develop a new gene therapy to promote cone survival in patients with RP. If benefit is demonstrated in preserving cones in patients with RP, a similar strategy could be tested in the future to see if it protects both rods and cones in patients with AMD. This study addresses a major public health problem in the US, inherited retinal degenerations, for which there is currently no effective treatment. In addition, the results may also be applicable to AMD, the most prevalent cause of severe vision loss in Americans over the age of 60.
