Abstact

Light initiates visual perception, but it also exacerbates a subset of blinding diseases in which visual (retinoid) cycle metabolic intermediates contribute to pathophysiology. Small molecule visual cycle modulators (VCMs) have demonstrated efficacy in preclinical models, but have been limited clinically by chronic, indiscriminate visual cycle suppression leading to side effects including night blindness in human subjects. Here, we demonstrate VCMs that are activated via a Z-->E photoisomerization of an azobenzene-containing VCM by visible light within the eye. One such VCM photoswitch, (Z)-9, is a weak inhibitor of the visual cycle isomerohydrolase, RPE65, that affords potent, rapid, and on-demand inhibition when photoisomerized to the E-configuration by visible light. (E)-9 protects the retina from visual cycle toxicity and, after oral administration, shows a shorter pharmacodynamic duration than emixustat as measured by electroretinography. These results establish posterior-segment photopharmacology and outline a blueprint for light-activated therapies that mitigate daytime toxicity while sparing night vision.