Cited by 229Retinal Development and DisordersRetinal Diseases and TreatmentsRetinoids in leukemia and cellular processes

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Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration

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Radu, Roxana A., Mata, Nathan L., Nusinowitz, Steven, Liu, Xinran, Sieving, Paul A., Travis, Gabriel H.·2003·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0737855100PMC PMC153626

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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.

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Authors: Radu, R. A., Mata, N. L., Nusinowitz, S., Liu, X., Sieving, P. A., & Travis, G. H.
Affiliations: National Institutes of Health (US)
ORCID: Radu, Roxana A.
Liu, Xinran
Sieving, Paul A.
Travis, Gabriel H.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2003-04
Volume: 100
Issue: 8
Pages: 4742-4747
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0737855100
PMC: PMC153626
OpenAlex: W2127150613
Cited by: 227
References: 43
Citations by year: 2026: 3 · 2025: 4 · 2024: 3 · 2023: 8 · 2022: 7 · 2021: 10 · 2020: 11 · 2019: 5 · 2018: 8 · 2017: 6 · 2016: 8 · 2015: 13 · 2014: 11 · 2013: 8 · 2012: 14
FWCI: 5.30
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
Keywords: isotretinoin, lipofuscin accumulation, A2E, retinal pigment epithelium, visual cycle, rhodopsin regeneration
MeSH terms: Animals, Dark Adaptation, Disease Models, Animal, Genes, Recessive, Humans, Lipofuscin, Macular Degeneration, Microscopy, Electron, Models, Biological, Pigment Epithelium of Eye, Pyridinium Compounds, Retinal Pigments, Retinoids, Rod Cell Outer Segment, Isotretinoin, Mice, Knockout, ATP-Binding Cassette Transporters, Mice

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Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration

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