Visual Cycle Modulation as an Approach toward Preservation of Retinal Integrity

PLoS One. 2015 May 13;10(5):e0124940. doi: 10.1371/journal.pone.0124940. eCollection 2015.


Increased exposure to blue or visible light, fluctuations in oxygen tension, and the excessive accumulation of toxic retinoid byproducts places a tremendous amount of stress on the retina. Reduction of visual chromophore biosynthesis may be an effective method to reduce the impact of these stressors and preserve retinal integrity. A class of non-retinoid, small molecule compounds that target key proteins of the visual cycle have been developed. The first candidate in this class of compounds, referred to as visual cycle modulators, is emixustat hydrochloride (emixustat). Here, we describe the effects of emixustat, an inhibitor of the visual cycle isomerase (RPE65), on visual cycle function and preservation of retinal integrity in animal models. Emixustat potently inhibited isomerase activity in vitro (IC50 = 4.4 nM) and was found to reduce the production of visual chromophore (11-cis retinal) in wild-type mice following a single oral dose (ED50 = 0.18 mg/kg). Measure of drug effect on the retina by electroretinography revealed a dose-dependent slowing of rod photoreceptor recovery (ED50 = 0.21 mg/kg) that was consistent with the pattern of visual chromophore reduction. In albino mice, emixustat was shown to be effective in preventing photoreceptor cell death caused by intense light exposure. Pre-treatment with a single dose of emixustat (0.3 mg/kg) provided a ~50% protective effect against light-induced photoreceptor cell loss, while higher doses (1-3 mg/kg) were nearly 100% effective. In Abca4-/- mice, an animal model of excessive lipofuscin and retinoid toxin (A2E) accumulation, chronic (3 month) emixustat treatment markedly reduced lipofuscin autofluorescence and reduced A2E levels by ~60% (ED50 = 0.47 mg/kg). Finally, in the retinopathy of prematurity rodent model, treatment with emixustat during the period of ischemia and reperfusion injury produced a ~30% reduction in retinal neovascularization (ED50 = 0.46mg/kg). These data demonstrate the ability of emixustat to modulate visual cycle activity and reduce pathology associated with various biochemical and environmental stressors in animal models. Other attributes of emixustat, such as oral bioavailability and target specificity make it an attractive candidate for clinical development in the treatment of retinal disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / deficiency
  • ATP-Binding Cassette Transporters / genetics
  • Animals
  • Disease Models, Animal
  • Electroretinography
  • Gene Expression
  • Light
  • Lipofuscin / antagonists & inhibitors
  • Lipofuscin / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / prevention & control
  • Phenyl Ethers / pharmacology*
  • Propanolamines / pharmacology*
  • Reperfusion Injury / drug therapy*
  • Reperfusion Injury / genetics
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Retinal Degeneration / drug therapy*
  • Retinal Degeneration / genetics
  • Retinal Degeneration / metabolism
  • Retinal Degeneration / pathology
  • Retinal Pigment Epithelium / drug effects
  • Retinal Pigment Epithelium / metabolism
  • Retinal Pigment Epithelium / pathology
  • Retinal Rod Photoreceptor Cells / drug effects*
  • Retinal Rod Photoreceptor Cells / metabolism
  • Retinal Rod Photoreceptor Cells / pathology
  • Retinoids / antagonists & inhibitors
  • Retinoids / metabolism
  • Retinopathy of Prematurity / drug therapy*
  • Retinopathy of Prematurity / genetics
  • Retinopathy of Prematurity / metabolism
  • Retinopathy of Prematurity / pathology
  • cis-trans-Isomerases / antagonists & inhibitors*
  • cis-trans-Isomerases / genetics
  • cis-trans-Isomerases / metabolism


  • A2-E (N-retinylidene-N-retinylethanolamine)
  • ATP-Binding Cassette Transporters
  • Abca4 protein, mouse
  • Lipofuscin
  • Phenyl Ethers
  • Propanolamines
  • Retinoids
  • emixustat
  • retinoid isomerohydrolase
  • cis-trans-Isomerases

Grant support

This work was funded through a joint collaboration between Acucela Inc. and Otsuka. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Otsuka did review the manuscript and had no comments. The granted funds were used to support costs of the research and salaries for authors CB, SHH, YZ, KM, TM, EB, AP, KLL, SZ, VK, MO, IS, AF and RK. The specific roles of these authors are articulated in the "author contributions" section.