Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells

Ivan Tochitsky; Aleksandra Polosukhina; Vadim E Degtyar; Nicholas Gallerani; Caleb M Smith; Aaron Friedman; Russell N Van Gelder; Dirk Trauner; Daniela Kaufer; Richard H Kramer

doi:10.1016/j.neuron.2014.01.003

Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells

Neuron. 2014 Feb 19;81(4):800-13. doi: 10.1016/j.neuron.2014.01.003.

Affiliations

¹ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
² Vision Science Graduate Group, University of California, Berkeley, Berkeley, CA 94720, USA.
³ Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁴ Departments of Ophthalmology, Pathology, and Biological Structure, University of Washington, Seattle, WA 98195, USA.
⁵ Department of Chemistry and Biochemistry, University of Munich, 81377 Munich, Germany.
⁶ Department of Integrative Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Helen Wills Neurosciences Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
⁷ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blindness / drug therapy
Blindness / physiopathology*
Disease Models, Animal
Electrophysiological Phenomena / physiology
Light
Mice
Mice, Inbred C57BL
Photoreceptor Cells / physiology*
Photosensitizing Agents / chemistry
Photosensitizing Agents / pharmacology
Retina / drug effects
Retina / physiopathology*
Retinal Degeneration / drug therapy
Retinal Degeneration / physiopathology*
Retinal Ganglion Cells / cytology
Retinal Ganglion Cells / physiology*
Treatment Outcome
Vision, Ocular / drug effects
Vision, Ocular / physiology*

Substances

Photosensitizing Agents

Restoring visual function to blind mice with a photoswitch that exploits electrophysiological remodeling of retinal ganglion cells

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding