title: Virally delivered channelrhodopsin-2 safely and effectively restores visual function in multiple mouse models of blindness.
abstract: Previous work established retinal expression of channelrhodopsin-2 (ChR2), an algal cation channel gated by light, restored physiological and behavioral visual responses in otherwise blind rd1 mice. However, a viable ChR2-based human therapy must meet several key criteria: (i) ChR2 expression must be targeted, robust, and long-term, (ii) ChR2 must provide long-term and continuous therapeutic efficacy, and (iii) both viral vector delivery and ChR2 expression must be safe. Here, we demonstrate the development of a clinically relevant therapy for late stage retinal degeneration using ChR2. We achieved specific and stable expression of ChR2 in ON bipolar cells using a recombinant adeno-associated viral vector (rAAV) packaged in a tyrosine-mutated capsid. Targeted expression led to ChR2-driven electrophysiological ON responses in postsynaptic retinal ganglion cells and significant improvement in visually guided behavior for multiple models of blindness up to 10 months postinjection. Light levels to elicit visually guided behavioral responses were within the physiological range of cone photoreceptors. Finally, chronic ChR2 expression was nontoxic, with transgene biodistribution limited to the eye. No measurable immune or inflammatory response was observed following intraocular vector administration. Together, these data indicate that virally delivered ChR2 can provide a viable and efficacious clinical therapy for photoreceptor disease-related blindness.
authors.affiliation: Eos Neuroscience, Inc, Los Angeles, California, USA.
authors.forename: M Mehdi
authors.initials: MM
authors.lastname: Doroudchi
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Greenberg
authors.forename: Jianwen
authors.initials: J
authors.lastname: Liu
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Silka
authors.forename: Edward S
authors.initials: ES
authors.lastname: Boyden
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Lockridge
authors.forename: A Cyrus
authors.initials: AC
authors.lastname: Arman
authors.forename: Ramesh
authors.initials: R
authors.lastname: Janani
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Boye
authors.forename: Sanford L
authors.initials: SL
authors.lastname: Boye
authors.forename: Gabriel M
authors.initials: GM
authors.lastname: Gordon
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Matteo
authors.forename: Alapakkam P
authors.initials: AP
authors.lastname: Sampath
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: Alan
authors.initials: A
authors.lastname: Horsager
mesh_terms: D000818:Animals; D019393:Arrestin / Q000378:metabolism; D001766:Blindness / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D000229:Dependovirus; D004594:Electrophysiology; D005904:Glial Fibrillary Acidic Protein; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D014785:Vision, Ocular / Q000235:genetics / Q000502:physiology
chemical_list: D019393:Arrestin; D002352:Carrier Proteins; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; C523009:channelopsin-2, Chlamydomonas reinhardtii; C528900:glial fibrillary astrocytic protein, mouse; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse