Evaluation of potential therapies for a mouse model of human age-related macular degeneration caused by delayed all-trans-retinal clearance.
Mo kle
Abstrè
OBJECTIVE
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, alpha-lipoic acid, alpha-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.
