Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization

Significance Accumulation of lipofuscin in the retinal pigment epithelium precedes retinal degenerations and dystrophies responsible for blindness-causing retinal diseases. The mechanism behind lipofuscin formation in the retina or in any tissue is poorly understood. Here we show in mice that the dimerization of vitamin A is responsible for triggering the formation of more than 50% of ocular lipofuscin. Replacing three hydrogen atoms on vitamin A with deuterium inhibits vitamin A dimerization, resulting in reduced lipofuscin and transcriptional normalization of genes associated with inflammation without compromising retinal function. Thus, vitamin A deuterated at the carbon 20 position provides a clinically amiable tool to prevent vitamin A dimerization in humans to assess whether impeding such dimerization might prevent retinal degenerations such as Stargardt disease and age-related macular degeneration.