RESTORATION OF VISUAL ACUITY AND VISUALLY GUIDED BEHAVIOR IN AMBIENT WHITE LIGHT WITH PHOTOSWITCHABLE SMALL MOLECULES

Blinding diseases caused by photoreceptor (PhR) degeneration, such as geographic atrophy (GA) secondary to dry age-related macular degeneration and retinitis pigmentosa (RP), leave most inner retinal circuitry structurally intact but unable to respond to light. Current therapeutic options remain limited. Gene therapy benefit only small, mutation-defined subsets of RP patients, while electronic retinal prostheses are invasive, costly, and provide limited visual resolution. Photopharmacology can develop photoswitchable small molecules to restore vision impairment by conferring light sensitivity to ion channels that are widely expressed in the remaining inner retinal neurons, and a first-in-human clinical trial is ongoing. Here, we developed novel photoswitchable small molecule ligands of metabotropic glutamate 6 (mGlu₆) receptors, which are located exclusively at the dendrites of ON bipolar cells (postsynaptic to PhRs), leveraging a privileged position to mimic physiological signals in the remnant retinal circuit. These photoswitchable ligands (prosthe6) act as 'molecular prostheses' and can restore the light input to the retina via upstream-targeted control of the circuit after PhRs degeneration. Prosthe6 are allosteric, drug-like, water soluble, and display outstanding in vitro properties including full efficacy, nanomolar potency, fast deactivation in ambient white light, and fast reactivation in the dark. In vivo experiments show recovery of visual acuity of blinded zebrafish larvae and restoration of innate light-avoidance behavior in mouse models of GA and RP, with effects confirmed to be mGlu₆ mediated. In addition, at least two compounds restore sight by topical administration and display promising safety properties, supporting their potential as drug candidates for degenerative blinding diseases.