title: Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells.
abstract: 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.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Tochitsky
authors.affiliation: Vision Science Graduate Group, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Polosukhina
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Vadim E
authors.initials: VE
authors.lastname: Degtyar
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Gallerani
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Caleb M
authors.initials: CM
authors.lastname: Smith
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Friedman
authors.affiliation: Departments of Ophthalmology, Pathology, and Biological Structure, University of Washington, Seattle, WA 98195, USA.
authors.forename: Russell N
authors.initials: RN
authors.lastname: Van Gelder
authors.affiliation: Department of Chemistry and Biochemistry, University of Munich, 81377 Munich, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Trauner
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Helen Wills Neurosciences Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kaufer
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Vision Science Graduate Group, University of California, Berkeley, Berkeley, CA 94720, USA; Helen Wills Neurosciences Institute, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: rhkramer@berkeley.edu.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Kramer
mesh_terms: D000818:Animals; D001766:Blindness / Q000188:drug therapy / Q000503:physiopathology*; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena / Q000502:physiology; D008027:Light; D051379:Mice; D008810:Mice, Inbred C57BL; D010786:Photoreceptor Cells / Q000502:physiology*; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology; D012160:Retina / Q000187:drug effects / Q000503:physiopathology*; D012162:Retinal Degeneration / Q000188:drug therapy / Q000503:physiopathology*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000502:physiology*; D016896:Treatment Outcome; D014785:Vision, Ocular / Q000187:drug effects / Q000502:physiology*
chemical_list: D017319:Photosensitizing Agents