Isotretinoin Treatment Inhibits Lipofuscin Accumulation in a Mouse Model of Recessive Stargardt's Macular Degeneration

  1. Gregory Bock Organizer,
  2. Gerry Chader Organizer and
  3. Jamie Goode
  1. Roxana A. Radu1,
  2. Nathan L. Mata1,
  3. Steven Nusinowitz1,
  4. Xinran Liu2 and
  5. Gabriel H. Travis3,*

Published Online: 7 OCT 2008

DOI: 10.1002/0470092645.ch5

Retinal Dystrophies: Functional Genomics to Gene Therapy: Novartis Foundation Symposium 255

Retinal Dystrophies: Functional Genomics to Gene Therapy: Novartis Foundation Symposium 255

How to Cite

Radu, R. A., Mata, N. L., Nusinowitz, S., Liu, X. and Travis, G. H. (2003) Isotretinoin Treatment Inhibits Lipofuscin Accumulation in a Mouse Model of Recessive Stargardt's Macular Degeneration, in Retinal Dystrophies: Functional Genomics to Gene Therapy: Novartis Foundation Symposium 255 (eds G. Bock, G. Chader and J. Goode), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/0470092645.ch5

Author Information

  1. 1

    Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, CA 90095, USA

  2. 2

    Center for Basic Neuroscience, UT Southwestern Medical Center, Dallas, TX 75235, USA

  3. 3

    Department of Biological Chemistry, UCLA School of Medicine, Los Angeles, CA 90095, USA

*Jules Stein Eye Institute, UCLA School of Medicine, 100 Stein Plaza, Room BH-667, Los Angeles, CA 90095, USA

  1. This paper is reproduced in modified form from Radu RA, Mata NL, Nusinowitz S, Liu X, Sieving PA, Travis GH 2003 Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. Proc Natl Acad Sci USA 100:4742–4747, with permission from the National Academy of Sciences, USA.

Publication History

  1. Published Online: 7 OCT 2008
  2. Published Print: 9 DEC 2003

Book Series:

  1. Novartis Foundation Symposia

Book Series Editors:

  1. Novartis Foundation

ISBN Information

Print ISBN: 9780470853573

Online ISBN: 9780470092644

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Summary

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 (RPE). This accumulation appears to be responsible for the photoreceptor death and severe visual loss in Stargardt's patients. Here, we tested a novel 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 (11cRAL) and regeneration of rhodopsin by inhibiting 11-cis-retinol dehydrogenase (11cRDH) in the visual cycle. Light activation of rhodopsin results in its release of all-trans-retinaldehyde (atRAL), 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.