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Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization
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Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization
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Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization
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Journal Article
Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization
2015
Overview
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-D â-vitamin A) impedes the dimerization rate of vitamin Aâby approximately fivefold for the vitamin A dimer A2Eâand subsequent lipofuscinogenesis and normalizes the aberrant transcription of complement genes without impairing retinal function. Phenotypic rescue by C20-D â-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-D â-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.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
/ age-related macular degeneration
/ ALK-001
/ Animals
/ ATP-Binding Cassette Transporters - genetics
/ ATP-Binding Cassette Transporters - metabolism
/ carbon
/ Genes
/ Macular Degeneration - congenital
/ Macular Degeneration - drug therapy
/ Macular Degeneration - genetics
/ Microscopy, Electron, Transmission
/ retina
/ Retinal Pigment Epithelium - drug effects
/ Retinal Pigment Epithelium - metabolism
/ Retinal Pigment Epithelium - ultrastructure
/ Rodents
/ vision
