Evaluation of 9-cis-Retinyl Acetate Therapy in Rpe65-/- Mice

• Published in: Investigative ophthalmology & visual science Vol. 50; no. 9; pp. 4368 - 4378
• Main Authors: Maeda, Tadao, Maeda, Akiko, Casadesus, Gemma, Palczewski, Krzysztof, Margaron, Philippe
• Format: Journal Article
• Language: English
• Published: Rockville, MD ARVO 01.09.2009; Association for Research in Vision and Ophtalmology
• Subjects: Animals; Behavior, Animal; Biological and medical sciences; Blindness - drug therapy; Blindness - genetics; Blindness - physiopathology; Carrier Proteins - genetics; cis-trans-Isomerases; Electroretinography - drug effects; Eye and associated structures. Visual pathways and centers. Vision; Eye Proteins - genetics; Fundamental and applied biological sciences. Psychology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Ophthalmology; Pharmaceutical Vehicles; Photic Stimulation; Prodrugs - administration & dosage; Retina - metabolism; Retina - physiopathology; Retina - radiation effects; Retinal Degeneration - drug therapy; Retinal Degeneration - genetics; Retinal Degeneration - physiopathology; Retinoids - metabolism; Soybean Oil - administration & dosage; Vertebrates: nervous system and sense organs; Vitamin A - administration & dosage; Vitamin A - analogs & derivatives; Evaluation; Vertebrata; Mammalia; Treatment; Mouse; Animal; Rodentia; Ophthalmology
• ISSN: 0146-0404; 1552-5783; 1552-5783
• DOI: 10.1167/iovs.09-3700

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.