Evaluation of potential therapies for a mouse model of human age-related macular degeneration caused by delayed all-trans-retinal clearance.

Abstract

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, 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.

• Authors: Tadao Maeda, Akiko Maeda, Melissa Matosky, Kiichiro Okano, Satsumi Roos, Johnny Tang, Krzysztof Palczewski
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 50 Issue 10 Pg. 4917-25 (Oct 2009) ISSN: 1552-5783 [Electronic] United States
• PMID: 19494204 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• A2-E (N-retinylidene-N-retinylethanolamine)
• ATP-Binding Cassette Transporters
• Abca4 protein, mouse
• Antioxidants
• Diterpenes
• Immunosuppressive Agents
• Pyridinium Compounds
• Retinoids
• Retinyl Esters
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Vitamin A
• retinol acetate
• retinylamine
• Alcohol Oxidoreductases
• Rdh8 protein, mouse

Topics

• ATP-Binding Cassette Transporters (genetics)
• Alcohol Oxidoreductases (genetics)
• Animals
• Antioxidants (therapeutic use)
• Dark Adaptation
• Diterpenes (therapeutic use)
• Electroretinography
• Female
• Fluorescein Angiography
• Immunosuppressive Agents (therapeutic use)
• Light
• Macular Degeneration (drug therapy, etiology, physiopathology)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Microscopy, Confocal
• Pyridinium Compounds (metabolism)
• Radiation Injuries, Experimental (drug therapy, etiology, physiopathology)
• Retina (metabolism, physiopathology, radiation effects)
• Retinoids (metabolism)
• Retinyl Esters
• Vascular Endothelial Growth Factor A (metabolism)
• Vitamin A (analogs & derivatives, metabolism, therapeutic use)