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Tadao Maeda, Akiko Maeda, Melissa Matosky, Kiichiro Okano, Satsumi Roos, Johnny Tang, Krzysztof Palczewski; Evaluation of Potential Therapies for a Mouse Model of Human Age-Related Macular Degeneration Caused by Delayed all-trans-Retinal Clearance. Invest. Ophthalmol. Vis. Sci. 2009;50(10):4917-4925. doi: 10.1167/iovs.09-3581.
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purpose. Evaluate the efficacy of potential therapeutics in Rdh8 −/− Abca4 −/− mice, a rodent model of human age-related macular degeneration (AMD).
methods. Therapeutic efficacy of several antioxidant agents (ascorbic acid, α-lipoic acid, α-tocopherol, Mn(III)-tetrakis(4-benzoic acid)-porphyrin, and butylated hydroxytoluene), an immunosuppressive agent with antivascular endothelial growth factor (VEGF) activity (sirolimus, also known as rapamycin), a retinoid cycle inhibitor (retinylamine), and an artificial chromophore (9-cis-retinyl acetate) were evaluated side by side in a recently described murine model of AMD, the Rdh8 −/− Abca4 −/− mouse. This animal exhibits a retinopathy caused by delayed all-trans-retinal clearance resulting from the absence of both ATP-binding cassette transporter 4 (Abca4) and retinol dehydrogenase 8 (Rdh8) activities. Drug efficacy was evaluated by retinal histologic analyses and electroretinograms (ERGs).
results. All tested agents partially prevented atrophic changes in the Rdh8 −/− Abca4 −/− retina with retinylamine demonstrating the greatest efficacy. A significant reduction of complement deposition on Bruch’s membrane was observed in sirolimus-treated mice, although the severity of retinal degeneration was similar to that observed in antioxidant- and 9-cis-retinyl acetate–treated mice. Sirolimus treatment of 6-month-old Rdh8 −/− Abca4 −/− mice for 4 months prevented choroidal neovascularization without changing retinal VEGF levels.
conclusions. Mechanism-based therapy with retinylamine markedly attenuated degenerative retinopathy in Rdh8 −/− Abca4 −/− mice. Further understanding of pathogenic mechanisms involved in AMD is needed to develop more effective therapeutics.
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