Abstract
SummaryMany retinal dystrophies result in photoreceptor loss, but the inner retinal neurons can survive, making them potentially amenable to emerging optogenetic therapies. Here, we show that ectopically expressed human rod opsin, driven by either a non-selective or ON-bipolar cell-specific promoter, can function outside native photoreceptors and restore visual function in a mouse model of advanced retinal degeneration. Electrophysiological recordings from retinal explants and the visual thalamus revealed changes in firing (increases and decreases) induced by simple light pulses, luminance increases, and naturalistic movies in treated mice. These responses could be elicited at light intensities within the physiological range and substantially below those required by other optogenetic strategies. Mice with rod opsin expression driven by the ON-bipolar specific promoter displayed behavioral responses to increases in luminance, flicker, coarse spatial patterns, and elements of a natural movie at levels of contrast and illuminance (≈50–100 lux) typical of natural indoor environments. These data reveal that virally mediated ectopic expression of human rod opsin can restore vision under natural viewing conditions and at moderate light intensities. Given the inherent advantages in employing a human protein, the simplicity of this intervention, and the quality of vision restored, we suggest that rod opsin merits consideration as an optogenetic actuator for treating patients with advanced retinal degeneration.
Highlights
IntroductionInherited retinal degenerations (retinal dystrophies), such as retinitis pigmentosa, affect 1:2,500 people worldwide
Inherited retinal degenerations, such as retinitis pigmentosa, affect 1:2,500 people worldwide
We show that ectopically expressed human rod opsin, driven by either a nonselective or ON-bipolar cell-specific promoter, can function outside native photoreceptors and restore visual function in a mouse model of advanced retinal degeneration
Summary
Inherited retinal degenerations (retinal dystrophies), such as retinitis pigmentosa, affect 1:2,500 people worldwide. Pioneering work has shown that electrophysiological responses to light can be restored to animal models of retinal degeneration by introducing a variety of optogenetic actuators to the surviving inner retina, including the mammalian photopigment melanopsin [4], prokaryotic photoactivated ion channels or pumps [5,6,7,8,9,10], synthetic light switches [11,12,13,14], and a synthetic photopigment (Opto-mGluR6) [15]. In most cases, these actuators function only under very bright light, and, to date, no clinically achievable optogenetic intervention has recreated spatiotemporal discrimination at commonly encountered light levels
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