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Gustavo D. Aguirre, Artur V. Cideciyan, Alfred S. Lewin, Simone Iwabe, Hemant Khanna, Anand Swaroop, William W. Hauswirth, Samuel G. Jacobson, William A. Beltran; Successful Photoreceptor-Directed Gene Therapy with AAV2/5-hRPGR Reverses Post-Receptoral Remodeling in Canine Models of X-linked RP. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5626.
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RGPR mutations account for the majority of severe retinal degeneration in X-linked RP and a significant fraction of simplex RP. Two different naturally-occurring RPGRORF15 mutations in dogs also cause severe retinal degenerative diseases that involve photoreceptor (PR) loss and secondary inner retinal remodeling. To assess gene therapy for clinical applications, we examined the effects on the inner retina of PR-directed gene augmentation.
AAV2/5 vectors with full-length human RPGRORF15 regulated by hIRBP or hGRK1 promoters were injected subretinally before disease onset (28 wks-XLPRA1) or in early stages of PR degeneration (5 wks-XLPRA2), and animals terminated at an age when degeneration is present in untreated eyes (77 and 38 wks). Non-invasive assessment (OCT, ERG) complemented morphologic and IHC analyses.
Treated areas showed preserved outer nuclear layer thickness and inner/outer segment reflectivity by in vivo imaging while neighboring untreated regions had severe degeneration. Rod PR function, and rod and cone post-receptoral b-wave responses were greater in most treated eyes compared to controls. Treatment before disease onset prevented PR degeneration in XLPRA1, and restored to normal the structure of the remaining PRs in XLPRA2. In treated areas outer plexiform layer (OPL) thickness was preserved, and retraction of bipolar cell dendrites identified with Goa and PKCa was reversed. GFAP immunolabeling clearly delineated untreated regions with increased Müller glia reactivity, whereas labeling diminished in the transition zone, and was absent in the treated area.
Treatment with full-length human RPGRORF15 restores OPL and inner retinal integrity. Our studies demonstrate for the first time the potential for halting the inner retinal remodeling events that result from PR loss, and thus makes effective treatment possible.
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