Evaluation of potential therapies for a mouse model of human age-related macular degeneration caused by delayed all-trans-retinal clearance.
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.
Maeda
Tadao
T
Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106, USA. txm88@case.edu
Maeda
Akiko
A
Matosky
Melissa
M
Okano
Kiichiro
K
Roos
Satsumi
S
Tang
Johnny
J
Palczewski
Krzysztof
K
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000429:Alcohol Oxidoreductases / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D003623:Dark Adaptation; D004224:Diterpenes / Q000627:therapeutic use*; D004596:Electroretinography; D005260:Female; D005451:Fluorescein Angiography; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008027:Light; D008268:Macular Degeneration / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D011726:Pyridinium Compounds / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D012160:Retina / Q000378:metabolism / Q000503:physiopathology / Q000528:radiation effects*; D012176:Retinoids / Q000378:metabolism; D000084562:Retinyl Esters; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use
D018528:ATP-Binding Cassette Transporters; D000429:Alcohol Oxidoreductases; D000975:Antioxidants; D004224:Diterpenes; D007166:Immunosuppressive Agents; D011726:Pyridinium Compounds; D012176:Retinoids; D000084562:Retinyl Esters; D042461:Vascular Endothelial Growth Factor A; D014801:Vitamin A; C112040:A2-E (N-retinylidene-N-retinylethanolamine); C512841:Abca4 protein, mouse; C467480:vascular endothelial growth factor A, mouse; C009166:retinol acetate; C009167:retinylamine; C525880:HSD17B6 protein, mouse