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Lolita Petit, Elsa Lhériteau, Michel Weber, Guylène Le Meur, Jack-Yves Deschamps, Philippe Moullier, Fabienne Rolling; AAV-mediated gene therapy restores retinal function and vision in the RPGRIP1-deficient dog. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5968.
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© ARVO (1962-2015); The Authors (2016-present)
Recently, gene therapy targeting photoreceptors was successfully used in canine models of rod-cone dystrophies, supporting the translation of this therapy to the clinic. In contrast, evidence of the efficacy of photoreceptors gene therapy in a large animal model of cone-rod dystrophies is still lacking. The aim of this study was to evaluate gene addition therapy in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1)-deficient miniature longhaired dachshund, a well characterized dog model of cone-rod dystrophy.
We generated AAV2/5 and AAV2/8 vectors carrying the canine Rpgrip1 cDNA under the control of the photoreceptor-specific rhodopsin kinase promoter. These vectors were subretinally injected to 1 eye of 4 RPGRIP1-deficient dogs at 1 month of age (AAV2/5, n=2 - AAV2/8, n=2). One AAV2/5-treated dog was sacrificed at 1 month postinjection and Rpgrip1 expression was assessed by RT-PCR on both treated and untreated retinas. In the 3 remaining treated dogs, funduscopy, optical coherence tomography, full-field electroretinography and behavioral tests were used to evaluate outcomes of AAV-mediated gene transfer.
RT-PCR analysis demonstrated an efficient expression of Rpgrip1 in the AAV2/5-treated RPGRIP-/- retina. Morphological analysis revealed a significant preservation of the retinal thickness and vasculature in both AAV2/5- and AAV2/8 -treated retinas. In all treated eyes, substantial cone-derived ERG responses were recorded as soon as 1 month postinjection (30 to 70% of those recorded in normal eyes) and remained stable for at least 12 months, whereas cone function was undetectable in untreated contralateral eyes. This rescue of cone function was accompanied by a significant preservation of rod function in 2/3 dogs at 12 months post-treatment (17 and 47% of those recorded at 1 month postinjection). At this age, rod function was totally lost in untreated contralateral eyes. Most importantly, both bright and dim-light vision was restored in all treated dogs.
These results provide for the first time compelling evidence that gene therapy can effectively restore retinal function and vision in a large animal model of cone-rod dystrophy. It represents a key step toward the clinic.
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