The functional characteristics of optogenetic gene therapy for vision restoration

Abstract

Optogenetic strategies to restore vision in patients blind from end-stage retinal degenerations aim to render remaining retinal neurons light-sensitive. We present an innovative combination of multi-electrode array recordings together with a complex pattern-generating light source as a toolset to determine the extent to which neural retinal responses to complex light stimuli can be restored following viral delivery of red-shifted channelrhodopsin in the retinally degenerated mouse. Our data indicate that retinal output level spatiotemporal response characteristics achieved by optogenetic gene therapy closely parallel those observed for normal mice but equally reveal important limitations, some of which could be mitigated using bipolarcell targeted gene-delivery approaches. As clinical trials are commencing, these data provide important new information on the capacity and limitations of channelrhodopsin-based gene therapies. The toolset we established enables comparing optogenetic constructs and stem-cell-based techniques, thereby providing an efficient and sensitive starting point to identify future approaches for vision restoration.

A systematic comparison of optogenetic approaches to visual restoration

“…There is an increasing body of evidence to suggest that intraretinal signal processing can be maintained by targeting surviving upstream retinal neurons, especially bipolar cells. 13 , 17 , 18 , 19 , 29 The flatter stimulus intensity-response relationship and shorter decay time further support ON bipolar cells as favorable targets for optogenetic vision restoration. Despite recent advances, 30 obtaining such targeted expression within bipolar cells remains challenging.…”

“…This is additionally interesting in the context of previous observations that ReaChR is better able to track sinusoidal stimuli when targeted to an L7-positive bipolar population, compared with non-specific delivery. 13 These findings would imply a better temporal resolution and would warrant further development, given the need for such resolution for the restoration of naturalistic vision.…”

“… 1 The development of a clinical retinal gene replacement therapy based on an adeno-associated viral (AAV) delivery system 2 has heightened the drive to develop mutation-independent approaches to restoring vision, which may be applicable even after photoreceptors are lost. Optogenetics, the introduction of transgenic protein tools rendering targeted cells photosensitive, has been demonstrated in preclinical models to restore light responses using a variety of optogenetic tools 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 and has entered early-phase clinical trials (ClinicalTrials.gov: NCT02556736 and NCT03326336; clinicaltrials.gov ). Indeed, Sahel et al.…”

“…However, reports in animal models have emerged demonstrating that useful intraretinal signaling processing can be retained when upstream retinal neurons are targeted specifically: in particular, that ON- and OFF-type responses can be restored by targeting populations including retinal bipolar cells. 8 , 12 , 13 , 17 , 18 , 19 Beyond intraretinal signal processing, the cellular environment of the transduced cell type will impact how a particular optogenetic tool will function, and it is this combination that will ultimately define suitability for optogenetic therapy.…”

Red Light Optogenetics in Neuroscience

“…Other red light opsins have still been actively present in neuroscientific research. ReaChR and MCO have been utilized in the restoration of sight in mice ( Batabyal et al, 2020 ; Lindner et al, 2020 ). They have also had interesting utilities in pain research ( Narcisse et al, 2021 ; Yi et al, 2021 ).…”