The functional characteristics of optogenetic gene therapy for vision restoration

Moritz Lindner,Mark W Hankins,Stuart N Peirson,Michael J Gilhooley,Steven Hughes

doi:10.1007/s00018-020-03597-6

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 bipolar-cell 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.

Highlights

Degenerative retinal disorders are among the leading causes of blindness in industrial countries [1]
These mice have a non-sense mutation in the Pde6b gene, which leads to rapid degeneration of rod photoreceptors followed by cone loss [24]. rd1 mice were injected with AAV-ReaChR-mCitrine at the age of 6 weeks
Transduced cells were predominantly located in the ganglion cell layer (GCL), but to lesser extent in the inner nuclear layer (INL)

Summary

Introduction

Degenerative retinal disorders are among the leading causes of blindness in industrial countries [1]. A novel strategy involves the expression of transgenes encoding photosensitive proteins (translational optogenetics) in surviving retinal cells such as ganglion cells [5,6,7], bipolar cells [8,9,10,11,12] or outer segments degenerate photoreceptors [13], to make them directly light sensitive [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21] Such an optogenetic gene therapy is attractive as it does not depend on the integrity of the retinal pigment epithelium photoreceptor complex. Thereby it offers the potential to restore vision even in late-stage retinal degenerations, while other approaches aim only to arrest further visual loss [22] It can function independently of the underlying disease cause and could thereby represent an efficient way to offer a mutation-independent therapeutic option even to individuals affected by orphan retinal degenerative disorders

Methods

Results

Discussion

Conclusion