title: Restoration of visual function by expression of a light-gated mammalian ion channel in retinal ganglion cells or ON-bipolar cells.
abstract: Most inherited forms of blindness are caused by mutations that lead to photoreceptor cell death but spare second- and third-order retinal neurons. Expression of the light-gated excitatory mammalian ion channel light-gated ionotropic glutamate receptor (LiGluR) in retinal ganglion cells (RGCs) of the retina degeneration (rd1) mouse model of blindness was previously shown to restore some visual functions when stimulated by UV light. Here, we report restored retinal function in visible light in rodent and canine models of blindness through the use of a second-generation photoswitch for LiGluR, maleimide-azobenzene-glutamate 0 with peak efficiency at 460 nm (MAG0(460)). In the blind rd1 mouse, multielectrode array recordings of retinal explants revealed robust and uniform light-evoked firing when LiGluR-MAG0(460) was targeted to RGCs and robust but diverse activity patterns in RGCs when LiGluR-MAG0(460) was targeted to ON-bipolar cells (ON-BCs). LiGluR-MAG0(460) in either RGCs or ON-BCs of the rd1 mouse reinstated innate light-avoidance behavior and enabled mice to distinguish between different temporal patterns of light in an associative learning task. In the rod-cone dystrophy dog model of blindness, LiGluR-MAG0(460) in RGCs restored robust light responses to retinal explants and intravitreal delivery of LiGluR and MAG0(460) was well tolerated in vivo. The results in both large and small animal models of photoreceptor degeneration provide a path to clinical translation.
authors.affiliation: Helen Wills Neuroscience Institute, and.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Gaub
authors.affiliation: Departments of Molecular and Cell Biology and.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Berry
authors.affiliation: Departments of Molecular and Cell Biology and.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Holt
authors.affiliation: Departments of Molecular and Cell Biology and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiner
authors.affiliation: Departments of Molecular and Cell Biology and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kienzler
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Natalia
authors.initials: N
authors.lastname: Dolgova
authors.affiliation: Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Sergei
authors.initials: S
authors.lastname: Nikonov
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Aguirre
authors.affiliation: Section of Ophthalmology, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: William A
authors.initials: WA
authors.lastname: Beltran
authors.affiliation: Helen Wills Neuroscience Institute, and Departments of Molecular and Cell Biology and Optometry, University of California, Berkeley, CA 94720; flannery@berkeley.edu ehud@berkeley.edu.
authors.forename: John G
authors.initials: JG
authors.lastname: Flannery
authors.affiliation: Helen Wills Neuroscience Institute, and Departments of Molecular and Cell Biology and Physical Bioscience Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 flannery@berkeley.edu ehud@berkeley.edu.
authors.forename: Ehud Y
authors.initials: EY
authors.lastname: Isacoff
mesh_terms: D000818:Animals; D001766:Blindness / Q000503:physiopathology; D015640:Ion Channel Gating; D007473:Ion Channels / Q000502:physiology / Q000528:radiation effects*; D008027:Light; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012165:Retinal Ganglion Cells / Q000502:physiology / Q000528:radiation effects*; D014785:Vision, Ocular
chemical_list: D007473:Ion Channels
keywords: azobenzene photoswitches; optogenetic pharmacology; retinal gene therapy; retinitis pigmentosa; visual prosthetics