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GM Acland, GD Aguirre, TS Aleman, AV Cideciyan, AM Maguire, SG Jacobson, WW Hauswirth, J Bennett; Continuing Evaluation of Gene Therapy In The Rpe65 Mutant Dog . Invest. Ophthalmol. Vis. Sci. 2002;43(13):4593.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:To evaluate the long term effects on visual function of intraocular delivery of rAAV-RPE65 to RPE65 mutant dogs, a naturally occurring model of human Leber congenital amaurosis. Methods: As part of our earlier study, three RPE65 mutant dogs were injected, subretinally in one eye and intravitreally in the contralateral eye, with a recombinant adeno-associated virus carrying a chicken beta-actin promoter-driven canine cDNA encoding wildtype RPE65 (rAAV-RPE65). Restoration of visual function was demonstrated in the subretinally injected eyes 3 months after the injection (Acland at al., 2001).Two of these dogs are now studied at 13 months post-treatment. Dark-adapted ERG b-wave intensity response series were obtained; ERG photoresponses were recorded and fitted with a phototransduction model to quantify photoreceptor function. Light-adapted 29 Hz flicker was used to isolate cone function. Visually guided behaviour was also evaluated clinically. Results:The remarkable improvement in ERG parameters observed in subretinally injected eyes at 3 months remained unchanged 10 months later. ERG b-wave thresholds in these eyes were 3-4 log units lower than untreated eyes. Photoresponse amplitudes were substantial and sensitivity was close to the normal range. Cone 30Hz flicker was clearly detected. In contrast, ERGs of intravitreally injected eyes remained similar to those of untreated RPE65 deficient eyes: ERG b-wave thresholds were markedly elevated; small photoresponses were only detectable at the highest intensity; and cone flicker was not detectable. Behavioral assessment supported the ERG findings. Conclusion: The restoration of visual function in the RPE65 mutant dog achieved by subretinal delivery of rAVV-RPE65 persists for at least 13 months post-treatment and the magnitude of this effect is unchanged.
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