A novel non-invasive photoswitchable molecule restores light sensitivity and visual acuity in blind animal models

Some blinding disorders, such as retinitis pigmentosa (RP), cause a complete degeneration of photoreceptors, resulting in loss of visual function while preserving the inner retinal circuitry. Approaches including implanted electrodes or gene therapy have demonstrated certain benefits, but they rely on invasive and costly procedures. In contrast, photopharmacology has achieved the development of small photoswitchable compounds capable of restoring visual responses by providing light sensitivity to ion channels in the remaining retinal cells. The aim of this study is to introduce a novel photoswitchable molecule that successfully restores light sensitivity and visual acuity in blind animal models. Prosthe6 pharmacokinetics were evaluated in vitro. Optokinetic responses were assessed in blinded zebrafish larvae. Light avoidance assays and the Optomotor Test (OptoDrum) were performed to evaluate the recovery of light-driven behavior and visual acuity in a mouse model of RP, after topical administration of the compound. In vitro analyses revealed that prosthe6 compounds were water-soluble and acted allosterically, exhibiting nanomolar potency, rapid deactivation and reactivation under ambient white light and darkness, respectively, and adequate solubility for topical delivery. In vivo studies demonstrated recovery of edge-detection capacity in blinded zebrafish. Light avoidance test showed that in the retinitis pigmentosa mouse model, prosthe6 restored light-driven behavior, and now animals were able to identify the illuminated compartment. With the OptoDrum setup, we were able to see that treated animals perceived optomotor characteristic stimuli (black and white gratings with different spatial frequencies and contrast), indicating a substantial improvement in visual acuity. This innovative photoswitchable compound achieved restoration of edge detection, light responsiveness, and visual acuity in blind animal models following topical administration. Prosthe6 represents a promising therapeutic strategy for vision restoration in retinal neurodegenerative diseases.