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Tadao Maeda, Akiko Maeda, Gemma Casadesus, Krzysztof Palczewski, Philippe Margaron; Evaluation of 9-cis-Retinyl Acetate Therapy in Rpe65−/− Mice. Invest. Ophthalmol. Vis. Sci. 2009;50(9):4368-4378. doi: 10.1167/iovs.09-3700.
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purpose. Mice lacking retinal pigment epithelium–specific 65-kDa protein (RPE65) develop retinopathy and blindness resembling Leber congenital amaurosis. Effects of 9-cis-retinyl acetate (9-cis-R-Ac) on visual function and retinopathy progression were tested in Rpe65 −/− mice.
methods. Young C57Bl/6 mice were given 9-cis-R-Ac in each of four different oil-based vehicle solutions by gastric gavage to identify the vehicle most suitable for drug delivery by measuring retinoid levels in plasma. Then doses of 9-cis-R-Ac ranging from 1 to 100 mg/kg were administered to 5- to 12-week-old Rpe65 −/− mice by different treatment regimens, including single doses and either intermittent or daily doses for various periods up to 8 weeks. Retinoid effects on visual function were evaluated by electroretinography, retinoid analyses, histologic methods, and vision-dependent behavioral testing.
results. Soybean oil vehicle provided the highest 9-cis-R-Ac metabolite levels in plasma. Single doses of 9-cis-R-Ac (6.25–50 mg/kg) provided significant dose-dependent improvement in electroretinographic responses. Well-tolerated daily doses (1–12.5 mg/kg) for 2 weeks induced remarkable improvement of retinal function. Significant dose-dependent improvement of electroretinographic responses was observed 6 days after administration of 9-cis-R-Ac daily for 3 days at 1 to 12.5 mg/kg. Mice given either daily or intermittent 9-cis-R-Ac treatment at 1 and 4 mg/kg and evaluated 8 weeks later displayed dose-dependent improvement of retinal function and morphology, whereas retinal function deteriorated in control animals. Treated mice also performed better than control animals in vision-dependent behavioral tests.
conclusions. Treatment with 9-cis-R-Ac improves visual function and preserves retinal morphology in Rpe65 −/− mice.
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