Article

Gene therapy restores vision in a canine model of childhood blindness

James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
Nature Genetics (Impact Factor: 29.65). 06/2001; 28(1):92-5. DOI: 10.1038/88327
Source: PubMed

ABSTRACT 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 photoreceptor and RPE diseases that cause blindness have been identified. Gene therapy has been used successfully to slow degeneration in rodent models of primary photoreceptor diseases, 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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    • "Natural Mendelian dog mutants have been bred to study diseases such as muscular dystrophy and an early-onset childhood retinal dystrophy that can result from mutation in one of several genes (Leber congenital amaurosis). Both those models have shown significant clinical improvement, with gene therapy addressing the pathological mutations of Dystrophin and RPE65, respectively (Acland et al. 2001; Bainbridge et al. 2008 "
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    • "The sensitivity of the conventional ERG is also limited because of the distance between the recording electrode placed on the surface of the cornea and the retina where the ERG signals originate (Brown, 1968). Consequently, subjects with profoundly depressed ERG responses can retain significant visually mediated behavior (Acland et al., 2001; Melillo et al., 2012; Narfstrom et al., 2003a, b). In addition, the PLR can be elicited with significantly dimmer stimuli than can the ERG (Whiting et al., 2013c; Yao et al., 2006). "
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    • "Loss of function prior to marked degeneration of photoreceptors provides a ''window of opportunity'' for gene augmentation therapy. The initial proof-of-principle studies in young Rpe65-deficient dogs showed that subretinally delivered recombinant adeno-associated viral (rAAV) vectors expressing either human or canine RPE65 dramatically improved photoreceptor function as assessed by ERG, vision-testing performance, and retinal-mediated visual cortex activity (Acland et al., 2001; Narfströ m et al., 2003; Acland et al., 2005; Aguirre et al., 2007). Similar dramatic improvements in retinal function were achieved in young Rpe65-/- and Rpe65 rd12/rd12 mice treated by rAAV-RPE65 subretinal injection (Dejneka et al., 2004; Pang et al., 2006; Roman et al., 2007; Bennicelli et al., 2008). "
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