Restoration of edge detection and visually guided behavior in ambient white light with photoswitchable small molecules

Blinding diseases due to degeneration of photoreceptors (PhRs) like geographic atrophy (GA) secondary to dry age-related macular degeneration (AMD) and retinitis pigmentosa (RP) leave the rest of the retinal circuitry largely intact, albeit unable to respond to light. Gene therapy has been able to revert PhR degeneration, but it can only be applied to a rare mutation affecting a small subset of RP patients. Alternatively, implanted electronic retinal prostheses aim at a larger population by electrically stimulating the surviving neurons. However, the treatment is invasive, costly, and provides limited 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-inhuman clinical trial is ongoing. Here, we have 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) and can leverage a privileged position to mimic physiological signals in the remnant retinal circuit. These photoswitchable ligands (prosthe6) thus act as ’molecular prostheses’ that can restore the light input to the retina via upstream-targeted control of the circuit after PhRs degeneration. Prosthe6 compounds 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 that they readily recover the edge detection ability of blinded zebrafish larvae and restore the innate light avoidance behavior in mouse models of blindness (GA and RP). These effects are mediated by mGlu6 receptors in vivo. In addition, at least two compounds (prosthe6-12 and-15) can restore sight by topical administration and display promising safety properties to become potential drug candidates for sight restoration in patients of degenerative blinding diseases.