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

Radu, Roxana A.; Mata, Nathan L.; Nusinowitz, Steven; Liu, Xinran; Sieving, Paul A.; Travis, Gabriel H.

doi:10.1073/pnas.0737855100

Cited by 208 publications

(152 citation statements)

References 35 publications

Supporting

Mentioning

149

Contrasting

Unclassified

Order By: Relevance

“…Our results show large amounts of A2E accumulation in ELOVL4 mutant mice compared with undetectable amounts in littermate controls. In the Abca4 knockout mouse, which is a model for recessive Stargardt macular degeneration, A2E-containing lipofuscin is also present in the RPE (26,27). The ELOVL4-transgenic mouse thus represents a second model of Stargardt macular degeneration showing a deleterious RPE accumulation of A2E-containing lipofuscin; although the ELOVL4-transgenic mice appear to accumulate manyfold more A2E than Abca4 knockout mice.…”

Section: Discussionmentioning

confidence: 99%

Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: A model for macular degeneration

Karan

Lillo

Yang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

169

176

View full text Add to dashboard Cite

Macular degeneration is a heterogeneous group of disorders characterized by photoreceptor degeneration and atrophy of the retinal pigment epithelium (RPE) in the central retina. An autosomal dominant form of Stargardt macular degeneration (STGD) is caused by mutations in ELOVL4, which is predicted to encode an enzyme involved in the elongation of long-chain fatty acids. We generated transgenic mice expressing a mutant form of human ELOVL4 that causes STGD. In these mice, we show that accumulation by the RPE of undigested phagosomes and lipofuscin, including the fluorophore, 2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetraenyl]-1-(2-hyydroxyethyl)-4-[4-methyl-6-(2,6,6,-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium (A2E) is followed by RPE atrophy. Subsequently, photoreceptor degeneration occurs in the central retina in a pattern closely resembling that of human STGD and age-related macular degeneration. The ELOVL4 transgenic mice thus provide a good model for both STGD and dry age-related macular degeneration, and represent a valuable tool for studies on therapeutic intervention in these forms of blindness.phagosome ͉ Stargardt disease ͉ photoreceptor ͉ retinal pigment epithelium M acular degeneration involves the death of photoreceptor cells in the central retina, which is responsible for fine-detail vision. Age-related macular degeneration (AMD) affects Ϸ30% of people over the age of 75 (1, 2), and is becoming a greater health problem with the rapidly growing elderly population of developed countries. There is no treatment to halt or reverse the disease for the dry form, which comprises Ϸ90% of AMD cases. Moreover, there is a lack of suitable animal models for experimentation on therapies for dry AMD. Stargardt macular dystrophy (STGD) shares pathological features with AMD, except that it occurs at a young age. Both AMD and STGD are characterized by the accumulation of high levels of lipofuscin in the retinal pigment epithelium (RPE), which precedes degeneration of the photoreceptors in the macula and RPE atrophy.The gene responsible for an autosomal dominant form of STGD, STDG3, was identified recently as ELOVL4 (3, 4). It is predicted to encode an enzyme involved in the elongation of very long-chain fatty acids (hence the name, ELOVL), and is highly expressed in rod and cone photoreceptor cells (5, 6). Sequence analysis of human ELOVL4 cDNA predicts a protein of 314 aa that shares homology with members of the yeast Elo (elongation of long chain fatty acid) family and the human ELO1 homolog (HELO1) (3). HELO1 and the ELO family members possess biochemical features that suggest their participation in reduction reactions occurring during fatty acid elongation (7,8). Mutational analysis of the ELOVL4 gene in five large STGD-like macular dystrophy pedigrees revealed a 5-bp deletion, resulting in a frame-shift and the introduction of a stop codon, 51 codons from the end of the coding region (3). Subsequently, two 1-bp deletions, 789delT and 794delT, in ELOVL4 were identifi...

show abstract

Section: Discussionmentioning

confidence: 99%

Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: A model for macular degeneration

Karan

Lillo

Yang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

169

176

View full text Add to dashboard Cite

show abstract

“…Isotretinoin (13-cis retinoic acid) acts as a blocker of the visual cycle because it inhibits RDH activity (Law and Rando, 1989); it reduces retinal damage from constant light exposure ) and reduces accumulation of lipofuscin in ABCA2-deficient mice (Radu et al, 2003). Another retinoid analog that inhibits the visual cycle is N-(4-hydroxyphenyl)retinamide (HPR).…”

Section: The Visual Cyclementioning

confidence: 99%

Seeing the light: New insights into the molecular pathogenesis of retinal diseases

Campochiaro

2007

Journal Cellular Physiology

View full text Add to dashboard Cite

In the past, most treatments for retinal diseases have been empirical. Steroids and/or laser photocoagulation and/or surgery have been tried for almost every condition with little or no understanding of the underlying disease. Over the past several years vision researchers have uncovered molecular components of processes, such as visual transduction and the visual cycle, that are critical for visual function, and identified other molecules that lead to dysfunction and disease processes such as neovascularization and macular edema. It is becoming clear that dysregulation of certain molecules can have major effects on retinal structure and function. Studies in animal models have suggested that inhibiting or augmenting levels of a single molecule can have major effects in complex disease processes. Although several molecules probably contribute to neovascularization and excessive vascular permeability in the eye, blockade of vascular endothelial growth factor (VEGF) has remarkable beneficial effects in animal models that have now been proven to apply to human diseases in clinical trials. Intraocular injection of VEGF antagonists has revolutionized the treatment of choroidal neovascularization (CNV) and macular edema and serves as a model of targeted ocular pharmacotherapy. Significant progress elucidating the molecular pathogenesis of several disease processes in the eye may soon lead to new treatments following the lead of VEGF antagonists. Initial treatments that provide benefit from frequent intraocular injections are likely to be followed by sustained delivery of drugs and/or prolonged protein delivery by gene transfer. The eye has entered the era of molecular therapy. J. Cell. Physiol. 213: 348–354, 2007. © 2007 Wiley‐Liss, Inc.

show abstract

“…In the studies of Radu et al (16), isotretinoin treatment retarded the formation of 11-cis-retinal, the photosensitive component of visual pigment that upon absorbing a photon undergoes isomerization to all-trans-retinal. Accordingly, both the WT and abcr null mutant mice exhibited isotretinoininduced delays in dark adaptation, a property that is sensitive to levels of visual pigment (rhodopsin, in the case of rods).…”

mentioning

confidence: 99%

“…Given the adverse effects of A2E, efforts to retard A2E deposition in RPE cells could serve to combat visual loss in Stargardt's disease. Thus it is significant that in this issue of PNAS, Radu et al (16) report that systemic drug therapy can reduce A2E accumulation in a mouse model of recessive Stargardt's disease (abcrϪ͞Ϫ).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Therapy for macular degeneration: Insights from acne

Sparrow

2003

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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

Cited by 208 publications

References 35 publications

Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: A model for macular degeneration

Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: A model for macular degeneration

Seeing the light: New insights into the molecular pathogenesis of retinal diseases

Therapy for macular degeneration: Insights from acne

Contact Info

Product

Resources

About