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Stargardt disease, an ATP-binding cassette, subfamily A, member 4 (ABCA4)-related retinopathy, is a genetic condition characterized by the accelerated accumulation of lipofuscin in the retinal pigment epithelium, degeneration of the neuroretina, and loss of vision. No approved treatment exists. Here, using a murine model of Stargardt disease, we show that the propensity of vitamin A to dimerize is responsible for triggering the formation of the majority of lipofuscin and transcriptional dysregulation of genes associated with inflammation. Data further demonstrate that replacing vitamin A with vitamin A deuterated at the carbon 20 position (C20-D3-vitamin A) impedes the dimerization rate of vitamin A--by approximately fivefold for the vitamin A dimer A2E--and subsequent lipofuscinogenesis and normalizes the aberrant transcription of complement genes without impairing retinal function. Phenotypic rescue by C20-D3-vitamin A was also observed noninvasively by quantitative autofluorescence, an imaging technique used clinically, in as little as 3 months after the initiation of treatment, whereas upon interruption of treatment, the age-related increase in autofluorescence resumed. Data suggest that C20-D3-vitamin A is a clinically amiable tool to inhibit vitamin A dimerization, which can be used to determine whether slowing the dimerization of vitamin A can prevent vision loss caused by Stargardt disease and other retinopathies associated with the accumulation of lipofuscin in the retina.

Original publication

DOI

10.1073/pnas.1506960112

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

07/07/2015

Volume

112

Pages

8415 - 8420

Keywords

A2E, ALK-001, C20-D3-vitamin A, age-related macular degeneration, bisretinoid, ATP-Binding Cassette Transporters, Animals, Deuterium, Dimerization, Electroretinography, Lipofuscin, Macular Degeneration, Mice, 129 Strain, Mice, Knockout, Microscopy, Electron, Transmission, Phenotype, Retina, Retinal Pigment Epithelium, Treatment Outcome, Vitamin A, Vitamins