Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization
Charbel Issa P., Barnard AR., Herrmann P., Washington I., MacLaren RE.
<jats:p>Stargardt disease, an ATP-binding cassette, subfamily A, member 4 (<jats:italic>ABCA4</jats:italic>)-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<jats:sub>3</jats:sub>-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-D<jats:sub>3</jats:sub>-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<jats:sub>3</jats:sub>-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.</jats:p>