title: Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization.
abstract: 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.
authors.affiliation: Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford and Oxford Eye Hospital, OX3 9DU, Oxford, United Kingdom; Department of Ophthalmology, University of Bonn, 53127 Bonn, Germany;
authors.forename: Peter
authors.identifier: http://orcid.org/0000-0002-0351-6673
authors.initials: P
authors.lastname: Charbel Issa
authors.affiliation: Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford and Oxford Eye Hospital, OX3 9DU, Oxford, United Kingdom;
authors.forename: Alun R
authors.identifier: http://orcid.org/0000-0002-0662-1073
authors.initials: AR
authors.lastname: Barnard
authors.affiliation: Department of Ophthalmology, University of Bonn, 53127 Bonn, Germany;
authors.forename: Philipp
authors.initials: P
authors.lastname: Herrmann
authors.affiliation: Department of Ophthalmology, Columbia University Medical Center, New York, NY 10032;
authors.forename: Ilyas
authors.initials: I
authors.lastname: Washington
authors.affiliation: Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford and Oxford Eye Hospital, OX3 9DU, Oxford, United Kingdom; Moorfields Eye Hospital and UCL Institute of Ophthalmology Biomedical Research Centre, EC1V 2PD, London, United Kingdom enquiries@eye.ox.ac.uk.
authors.forename: Robert E
authors.initials: RE
authors.lastname: MacLaren
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003903:Deuterium; D019281:Dimerization; D004596:Electroretinography; D008062:Lipofuscin / Q000096:biosynthesis; D008268:Macular Degeneration / Q000151:congenital* / Q000188:drug therapy / Q000235:genetics; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D010641:Phenotype; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D000080362:Stargardt Disease; D016896:Treatment Outcome; D014801:Vitamin A / Q000737:chemistry / Q000494:pharmacology*; D014815:Vitamins / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; C512841:Abca4 protein, mouse; D008062:Lipofuscin; D014815:Vitamins; D014801:Vitamin A; D003903:Deuterium
keywords: A2E; ALK-001; C20-D3-vitamin A; age-related macular degeneration; bisretinoid