Innovative Optogenetic Strategies for Vision Restoration

Abstract

The advent of optogenetics has ushered in a new era in neuroscience where spatiotemporal control of neurons is possible through light application. These tools used to study neural circuits can also be used therapeutically to restore vision. In order to recapitulate the broad spectral and light sensitivities along with high temporal sensitivity found in human vision, researchers have identified and developed new optogenetic tools. There are two major kinds of optogenetic effectors employed in vision restoration: ion channels and G-protein coupled receptors (GPCRs). Ion channel based optogenetic therapies require high intensity light that can be unsafe at lower wavelengths, so work has been done to expand and red-shift the excitation spectra of these channels. Light activatable GPCRs are much more sensitive to light than their ion channel counterparts but are slower kinetically in terms of both activation and inactivation. This review article examines the latest optogenetic ion channel and GPCR candidates for vision restoration based on light and temporal sensitivity.

Degeneration-Dependent Retinal Remodeling: Looking for the Molecular Trigger

“…Blocking or reducing hyperactivity unmasks light responses, opening a therapeutic window to enhance vision in patients suffering from RP, AMD and other photoreceptor degeneration diseases. In patients that are completely blind, restoration of vision might be possible through photo-pharmacology (Tochitsky et al, 2018), optogenetics (Baker and Flannery, 2018) or prosthetic devices (Mirochnik and Pezaris, 2019). However, low signal-to-noise ratio will result in poor visual restoration, regardless of the method employed.…”

The Optogenetic Revolution in Cerebellar Investigations

“…Indeed, recent constructs show reduced vector-associated cytotoxicity, suggesting that a clinical application in substitution to deep brain stimulation might be feasible soon. At the moment, optogenetics is applied only to vision restoration [166], but its overcoming of previous technical issues [167] might open several clinical applications in the field of cerebellum-related pathologies, also.…”

Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR

“…Currently, there is no treatment for RPGR related RP and despite proof of principle in animal models, 1 – 4 the effect of gene therapy targeting a photoreceptor degeneration (RP) in humans has not until now been reported. Amongst potential therapeutic approaches, 1 , 2 , 3 , 4 , 5 , 6 , 9 the most promising strategy for RPGR related RP is gene therapy using adeno-associated viral vector. 10 The recent approval of gene therapy for RPE65 related retinal degeneration 11 represents a significant advance in clinical medicine and offers the potential to correct many other inherited diseases.…”