NON-INVASIVE REHABILITATION OF LIGHT SENSITIVITY AND VISUAL ACUITY IN ANIMAL MODELS OF RETINAL DEGENERATION USING PHOTOSWITCHABLE DRUGS

Aim: Some blinding diseases, like retinitis pigmentosa (RP), show a complete degeneration of the photoreceptors, losing visual functions, but maintaining the rest of the retinal circuitry intact. Treatments like implanted electrodes or gene therapy provide some functional recovery but they are invasive, costly, and not applicable to all RP patients. In contrast, photoswitchable drugs allow to rehabilitate visual function by conferring light sensitivity to endogenous proteins in the remnant cells. We introduce new photoswitchable small molecules (Prosthe6) that restore light sensitivity and visual acuity in blinded animals by topical administration.
Methods: Compound pharmacokinetics was studied in rabbit. Recovery of optokinetic response was studied in blinded zebrafish larvae to screen the compounds. Recovery of light-driven behaviour and visual acuity in RP mouse model was assessed with the light avoidance test and the optomotor test, respectively.
Results: In vitro experiments demonstrate that Prosthe6 compounds are highly water-soluble, allosteric mechanism of action, nanomolar potency, fast deactivation and reactivation in ambient white light and darkness, respectively. They allow the recovery of edge detection ability in blinded zebrafish larvae. In RP model mice, Prosthe6 restore light-driven behaviour, and treated animals can detect optomotor characteristic stimuli, indicating a very important recovery of the visual acuity. They are notably active by topical administration.
Conclusions: Prosthe6 restore edge detection, visually guided behaviour and visual acuity in blinded animal models with topical administration. They offer inexpensive, self-administered treatment that can be applied to all RP patient profiles (mutation agnostic) and other retinal neurodegenerative pathologies to rehabilitate visual function.