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

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

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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Crossref · 10.1073/pnas.0737855100

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  • Isotretinoin impairs the chromophore 11-cis-retinal and slows rhodopsin regeneration, which can cause night blindness.

    “This impairs chromophore, 11-cis-retinal, and slows rhodopsin (RHO) regeneration which can cause night blindness.”

    From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [18]

  • Isotretinoin reduces the accumulation of toxic byproducts of the visual cycle, such as A2E.

    “However, on the other hand, it reduces the accumulation of toxic byproducts of the visual cycle, such as N-retinyl-N-retinylidene ethanolamine (A2E) [16,17,18].”

    From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [18]

  • In the RPE, isotretinoin inhibits two key visual cycle enzymes, RPE65 and 11-cis-retinol dehydrogenase.

    “In retina in the retinal pigment epithelium (RPE), isotretinoin inhibits two key visual cycle enzymes, RPE-specific 65 kDa protein (RPE65) [16] and 11-cis-retinol dehydrogenase [17,18] (Figure 1).”

    From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [18]

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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)
Venue
Proceedings of the National Academy of Sciences
Published
2003-04
Volume
100
Issue
8
Pages
4742-4747
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
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
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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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