Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration
- Roxana A. Radu*,
- Nathan L. Mata*,
- Steven Nusinowitz*,
- Xinran Liu†,
- Paul A. Sieving‡, and
- Gabriel H. Travis*,§,¶
- *Jules Stein Eye Institute and §Department of Biological Chemistry, University of California School of Medicine, Los Angeles, CA 90095; †Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75235; and ‡National Eye Institute, National Institutes of Health, Bethesda, MD 20892
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Edited by Thaddeus P. Dryja, Harvard Medical School, Boston, MA, and approved February 13, 2003 (received for review December 27, 2002)
Abstract
Recessive Stargardt's macular degeneration is an inherited blinding disease of children caused by mutations in the ABCR gene. The primary pathologic defect in Stargardt's disease is accumulation of toxic lipofuscin pigments such as N-retinylidene-N-retinylethanolamine (A2E) in cells of the retinal pigment epithelium. This accumulation appears to be responsible for the photoreceptor death and severe visual loss in Stargardt's patients. Here, we tested a therapeutic strategy to inhibit lipofuscin accumulation in a mouse model of recessive Stargardt's disease. Isotretinoin (Accutane) has been shown to slow the synthesis of 11-cis-retinaldehyde and regeneration of rhodopsin by inhibiting 11-cis-retinol dehydrogenase in the visual cycle. Light activation of rhodopsin results in its release of all-trans-retinaldehyde, which constitutes the first reactant in A2E biosynthesis. Accordingly, we tested the effects of isotretinoin on lipofuscin accumulation in abcr−/− knockout mice. Isotretinoin blocked the formation of A2E biochemically and the accumulation of lipofuscin pigments by electron microscopy. We observed no significant visual loss in treated abcr−/− mice by electroretinography. Isotretinoin also blocked the slower, age-dependent accumulation of lipofuscin in wild-type mice. These results corroborate the proposed mechanism of A2E biogenesis. Further, they suggest that treatment with isotretinoin may inhibit lipofuscin accumulation and thus delay the onset of visual loss in Stargardt's patients. Finally, the results suggest that isotretinoin may be an effective treatment for other forms of retinal or macular degeneration associated with lipofuscin accumulation.
Footnotes
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↵ ¶ To whom correspondence should be addressed at: Jules Stein Eye Institute, 100 Stein Plaza, University of California School of Medicine, Los Angeles, CA 90095. E-mail: travis{at}jsei.ucla.edu.
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This paper was submitted directly (Track II) to the PNAS office.
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See commentary on page 4353.
- Abbreviations:
- 11cRAL,
- 11-cis-retinaldehyde;
- 11cRDH,
- 11-cis-retinol dehydrogenase;
- 11cRE,
- 11-cis-retinyl ester;
- 11cROL,
- 11-cis-retinol;
- A2E,
- N-retinylidene-N-retinylethanolamine;
- A2PE-H2,
- dihydro-N-retinylidene-N-retinylphosphatidylethanolamine;
- atRAL,
- all-trans-retinaldehyde;
- atROL,
- all-trans-retinol;
- RPE,
- retinal pigment epithelium;
- N-ret-PE,
- N-retinylidene-phosphatidylethanolamine;
- ERG,
- electroretinography;
- mAU,
- milliabsorption units
- Copyright © 2003, The National Academy of Sciences
