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

Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8415-20. doi: 10.1073/pnas.1506960112. Epub 2015 Jun 23.


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.

Keywords: A2E; ALK-001; C20-D3-vitamin A; age-related macular degeneration; bisretinoid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Deuterium
  • Dimerization
  • Electroretinography
  • Lipofuscin / biosynthesis
  • Macular Degeneration / congenital*
  • Macular Degeneration / drug therapy
  • Macular Degeneration / genetics
  • Mice, 129 Strain
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Phenotype
  • Retina / drug effects
  • Retina / metabolism
  • Retina / physiopathology
  • Retinal Pigment Epithelium / drug effects*
  • Retinal Pigment Epithelium / metabolism
  • Retinal Pigment Epithelium / ultrastructure
  • Stargardt Disease
  • Treatment Outcome
  • Vitamin A / chemistry
  • Vitamin A / pharmacology*
  • Vitamins / chemistry
  • Vitamins / pharmacology


  • ATP-Binding Cassette Transporters
  • Abca4 protein, mouse
  • Lipofuscin
  • Vitamins
  • Vitamin A
  • Deuterium

Supplementary concepts

  • Stargardt disease 1