RESUMO
Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are blinding diseases caused by the degeneration of rods and cones, leaving the remainder of the visual system unable to respond to light. Here, we report a chemical photoswitch named DENAQ that restores retinal responses to white light of intensity similar to ordinary daylight. A single intraocular injection of DENAQ photosensitizes the blind retina for days, restoring electrophysiological and behavioral responses with no toxicity. Experiments on mouse strains with functional, nonfunctional, or degenerated rods and cones show that DENAQ is effective only in retinas with degenerated photoreceptors. DENAQ confers light sensitivity on a hyperpolarization-activated inward current that is enhanced in degenerated retina, enabling optical control of retinal ganglion cell firing. The acceptable light sensitivity, favorable spectral sensitivity, and selective targeting to diseased tissue make DENAQ a prime drug candidate for vision restoration in patients with end-stage RP and AMD.
Assuntos
Cegueira/fisiopatologia , Células Fotorreceptoras/fisiologia , Retina/fisiopatologia , Degeneração Retiniana/fisiopatologia , Células Ganglionares da Retina/fisiologia , Visão Ocular/fisiologia , Animais , Cegueira/tratamento farmacológico , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos/fisiologia , Luz , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Retina/efeitos dos fármacos , Degeneração Retiniana/tratamento farmacológico , Células Ganglionares da Retina/citologia , Resultado do Tratamento , Visão Ocular/efeitos dos fármacosRESUMO
Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are degenerative blinding diseases caused by the death of rods and cones, leaving the remainder of the visual system intact but largely unable to respond to light. Here, we show that AAQ, a synthetic small molecule photoswitch, can restore light sensitivity to the retina and behavioral responses in vivo in mouse models of RP, without exogenous gene delivery. Brief application of AAQ bestows prolonged light sensitivity on multiple types of retinal neurons, resulting in synaptically amplified responses and center-surround antagonism in arrays of retinal ganglion cells (RGCs). Intraocular injection of AAQ restores the pupillary light reflex and locomotory light avoidance behavior in mice lacking retinal photoreceptors, indicating reconstitution of light signaling to brain circuits. AAQ and related photoswitch molecules present a potential drug strategy for restoring retinal function in degenerative blinding diseases.