Evaluation of 9-cis-retinyl acetate therapy in Rpe65-/- mice.
OBJECTIVE
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.
Maeda
Tadao
T
Departments of Pharmacology.
Maeda
Akiko
A
Casadesus
Gemma
G
Palczewski
Krzysztof
K
Margaron
Philippe
P
D000818:Animals; D001522:Behavior, Animal; D001766:Blindness / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics*; D004224:Diterpenes; D004596:Electroretinography / Q000187:drug effects; D005136:Eye Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014677:Pharmaceutical Vehicles; D010775:Photic Stimulation; D011355:Prodrugs / Q000008:administration & dosage*; D012160:Retina / Q000378:metabolism / Q000503:physiopathology / Q000528:radiation effects; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D012176:Retinoids / Q000378:metabolism; D000084562:Retinyl Esters; D013024:Soybean Oil / Q000008:administration & dosage; D014801:Vitamin A / Q000008:administration & dosage / Q000031:analogs & derivatives*; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
D002352:Carrier Proteins; D004224:Diterpenes; D005136:Eye Proteins; D014677:Pharmaceutical Vehicles; D011355:Prodrugs; D012176:Retinoids; D000084562:Retinyl Esters; D013024:Soybean Oil; D014801:Vitamin A; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C009166:retinol acetate