Restoration of Vision and Retinal Responses After Adeno-Associated Virus–Mediated Optogenetic Therapy in Blind Dogs

Abstract

Purpose Optogenetic gene therapy to render remaining retinal cells light-sensitive in end-stage retinal degeneration is a promising strategy for treatment of individuals blind because of a variety of different inherited retinal degenerations. The clinical trials currently in progress focus on delivery of optogenetic genes to ganglion cells. Delivery of optogenetic molecules to cells in the outer neural retina is predicted to be even more advantageous because it harnesses more of the retinal circuitry. However, this approach has not yet been tested in large animal models. For this reason, we evaluated the safety and efficacy of optogenetic therapy targeting remaining diseased cone photoreceptors in the Rcd1 dog model of retinitis pigmentosa. Methods Imaging and measures of retinal function and functional vision were carried out, as well as terminal studies evaluating multi-electrode array recordings and histology. Results Animals remained healthy and active throughout the study and showed improved retinal and visual function as assessed by electroretinography and visual-evoked potentials, improved navigational vision, and improved function of cone photoreceptors and the downstream retinal circuitry. Conclusions The findings demonstrate that an optogenetic approach targeting the outer retina in a blind large animal model can partially restore vision. Translational Relevance This work has translational relevance because the approach could potentially be extrapolated to treat humans who are totally blind because of retinal degenerative disease.

Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development

“…This acquired properties of light-gated channels upon binding with maleimide-azobenzene-glutamate-0, showing evidence of derived light responses [ 177 ]. Similar delivery of optogenetic therapy targeting the outer retina was performed in Rdc1 dogs and C57BL/6 mice to investigate the differences in treatment on larger animals with higher life expectancy, showing a partial improvement in vision restoration through Y-maze performance and electroretinography [ 178 ].…”

Therapeutic landscape for inherited ocular diseases: current and emerging therapies

“…In a pre-clinical study where Rcd1 canine models received a unilateral subretinal injection containing the enhanced halorhodopsin cDNA from Natronomonas fused to the yellow fluorescent protein reporter gene, partial visual restoration was observed with promising results showing improved ERG, visual-evoked potential responses and visual navigation. [ 75 ]…”

Optogenetic Therapy for Visual Restoration

“…Hopefully, these new-generation AAV vectors with better transduction efficiency enable the conversion of a larger population of retinal cells into artificial photoreceptors and can be expected to provide higher quality vision to patients. As regards targeting deeper retinal cells, including bipolar cells and dormant cones, AAV8 [ 63 , 66 ] and its mutant (Y733F) [ 15 , 68 ] or AAV9 [ 61 , 62 ], administered through subretinal injection, have been used as other options.…”

“…While bipolar cells could be targeted through intravitreal injection with engineered AAV vectors [ 16 , 17 , 20 , 24 , 51 , 69 ], some researchers have reported successful transduction of bipolar cells through subretinal injection using AAV2(7m8) [ 20 ], AAV8(BP2) [ 20 ], or AAV8(Y733F) [ 15 ] with the Grm6 ON-bipolar cell promoter in RP mouse models. In contrast, subretinal injections have been used to rescue dormant cones [ 13 , 62 , 63 ].…”