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Gene therapy restores vision in a canine model of childhood blindness


The relationship between the neurosensory photoreceptors and the adjacent retinal pigment epithelium (RPE) controls not only normal retinal function, but also the pathogenesis of hereditary retinal degenerations. The molecular bases for both primary photoreceptor1 and RPE diseases2,3,4 that cause blindness have been identified. Gene therapy has been used successfully to slow degeneration in rodent models of primary photoreceptor diseases5,6, but efficacy of gene therapy directed at photoreceptors and RPE in a large-animal model of human disease has not been reported. Here we study one of the most clinically severe retinal degenerations, Leber congenital amaurosis (LCA). LCA causes near total blindness in infancy and can result from mutations in RPE65 (LCA, type II; MIM 180069 and 204100). A naturally occurring animal model, the RPE65−/− dog, suffers from early and severe visual impairment similar to that seen in human LCA. We used a recombinant adeno-associated virus (AAV) carrying wild-type RPE65 (AAV-RPE65) to test the efficacy of gene therapy in this model. Our results indicate that visual function was restored in this large animal model of childhood blindness.

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Figure 1: RPE65 immunocytochemistry in canine RPE cells and retinal sections.
Figure 2: Persistence and expression of the RPE65 transgene after in vivo delivery to neural retina (R) and RPE/choroid (P), and after in vitro delivery to RPE cells (RPE).
Figure 3: Restoration of retinal and visual function in RPE65 mutant dogs by subretinal AAV-RPE65.

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We thank G. Antonini, D. Beliaav, N. Bennett, V. Chiodo, A. Nickle, V. Rininger and V. Scarpino for technical assistance, and M. Maguire for statistical advice. Support from NIH grants EY10820, EY11123, NS36202, EY06855, EY11142 and EY13132, The Foundation Fighting Blindness, Research to Prevent Blindness, T.L. Andresen Endowment, the Macular Vision Research Foundation, the LIFE Foundation, the Steinbach Foundation, the Mackall Foundation Trust and the F.M. Kirby Foundation.

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Correspondence to Jean Bennett.

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Acland, G., Aguirre, G., Ray, J. et al. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28, 92–95 (2001).

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