Validation of mGlu6 as novel photoswitchable drug target to restore vision

In retinal degenerative diseases such as retinitis pigmentosa and age-related macular degeneration, the progressive loss of photoreceptor cells leads to irreversible blindness. However, most inner retinal neurons remain viable, enabling vision restoration by diverse approaches. Here, we present a drug-based strategy to restore sight that targets the metabotropic glutamate receptor 6 (mGlu6), which is specifically expressed in retinal ON bipolar neurons. We identify azobenzene-based compounds that act as mGlu6 photoswitchable agonists and positive allosteric modulators (ago-PAMs). One of them reversibly activates the receptor with light in the absence of glutamate, mimicking native phototransduction. In degenerated retinas from rd10 mice, it restores light-dependent firing patterns in retinal ganglion cells, including distinct ON and OFF responses, which indicate reactivation of the upstream retinal circuit and improved vision restoration signatures ex vivo. Intravitreal injection of the compound reinstates visually guided behavior (light avoidance) in chemically blinded mice. In acutely blinded zebrafish larvae, drug application rapidly and completely restores visual acuity measured by the optokinetic reflex. These findings validate mGlu6 as a novel drug target for vision restoration and identify the compound as the first one-component, receptor-targeted photoswitch capable of reactivating physiological retinal signaling. This work establishes a foundation to develop safe, reversible, and non-invasive pharmacological therapies to restore sight in blindness caused by photoreceptor degeneration.