The major objective of this proposal is to investigate therapeutic approaches for inherited photoreceptor degeneration. Murine models with defined genetic defects simulating human photoreceptor degeneration will serve as the primary experimental system with which to study the efficacy of replacement gene therapies. The gene defects to be studied are selected based on greater clinical significance as they cause severe forms of the disease and/or affect a large proportion of patients with photoreceptor degeneration. These studies will seek direct evidence that the gene replacement therapy will halt photoreceptor cell death even after such a process has begun in the retina, and will allow regrowth of photoreceptor outer segments and restoration of photoreceptor function. Issues relating to the efficient targeting of rod and cone photoreceptors and proof of efficacy with human gene constructs will be addressed. The outcomes of this research should provide the critical information necessary for a transition from genetic studies in animal models to future clinical applications of replacement gene therapy in patients with photoreceptor degeneration. ? ? ?
|Pawlyk, B S; Bulgakov, O V; Sun, X et al. (2016) Photoreceptor rescue by an abbreviated human RPGR gene in a murine model of X-linked retinitis pigmentosa. Gene Ther 23:196-204|
|Gilliam, Jared C; Chang, Juan T; Sandoval, Ivette M et al. (2012) Three-dimensional architecture of the rod sensory cilium and its disruption in retinal neurodegeneration. Cell 151:1029-41|
|Sun, X; Pawlyk, B; Xu, X et al. (2010) Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutations. Gene Ther 17:117-31|
|Liu, Xiaoqing; Pawlyk, Basil S; Adamian, Michael et al. (2009) Increased light exposure alleviates one form of photoreceptor degeneration marked by elevated calcium in the dark. PLoS One 4:e8438|
|Tan, Mei Hong; Smith, Alexander J; Pawlyk, Basil et al. (2009) Gene therapy for retinitis pigmentosa and Leber congenital amaurosis caused by defects in AIPL1: effective rescue of mouse models of partial and complete Aipl1 deficiency using AAV2/2 and AAV2/8 vectors. Hum Mol Genet 18:2099-114|