Maeda Tadao, Maeda Akiko, Casadesus Gemma, Palczewski Krzysztof, Margaron Philippe
Departments of Pharmacology.
Invest Ophthalmol Vis Sci. 2009 Sep;50(9):4368-78. doi: 10.1167/iovs.09-3700. Epub 2009 Apr 30.
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.
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.
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.
Treatment with 9-cis-R-Ac improves visual function and preserves retinal morphology in Rpe65(-/-) mice.
缺乏视网膜色素上皮特异性65 kDa蛋白（RPE65）的小鼠会发生视网膜病变并失明，类似于莱伯先天性黑蒙。在Rpe65基因敲除（Rpe65(-/-)）小鼠中测试了9-顺式视黄酸醋酸酯（9-顺式-R-Ac）对视觉功能和视网膜病变进展的影响。
给年轻的C57Bl/6小鼠通过灌胃给予四种不同油基载体溶液中的9-顺式-R-Ac，通过测量血浆中的类视黄醇水平来确定最适合药物递送的载体。然后，通过不同的治疗方案，包括单次给药以及长达8周的不同时间段的间歇或每日给药，将1至100 mg/kg剂量的9-顺式-R-Ac给予5至12周龄的Rpe65(-/-)小鼠。通过视网膜电图、类视黄醇分析、组织学方法和视觉依赖性行为测试来评估类视黄醇对视觉功能的影响。
大豆油载体在血浆中提供了最高的9-顺式-R-Ac代谢物水平。单次给予9-顺式-R-Ac（6.25 - 50 mg/kg）可使视网膜电图反应有显著的剂量依赖性改善。耐受良好的每日剂量（1 - 12.5 mg/kg）持续2周可显著改善视网膜功能。在以1至12.5 mg/kg每日给药3天的9-顺式-R-Ac给药后6天，观察到视网膜电图反应有显著的剂量依赖性改善。以1和4 mg/kg每日或间歇给予9-顺式-R-Ac治疗并在8周后评估的小鼠显示出视网膜功能和形态的剂量依赖性改善，而对照动物的视网膜功能恶化。在视觉依赖性行为测试中，治疗小鼠的表现也优于对照动物。
用9-顺式-R-Ac治疗可改善Rpe65(-/-)小鼠的视觉功能并保留视网膜形态。
