Abstract
The degeneration of light-detecting rod and cone photoreceptors in the human retina leads to severe visual impairment and ultimately legal blindness in millions of people worldwide. Multiple therapeutic options at different stages of degeneration are being explored but the majority of ongoing clinical trials involve adeno-associated viral (AAV) vector-based gene supplementation strategies for select forms of inherited retinal disease. Over 300 genes are associated with inherited retinal degenerations and only a small proportion of these will be suitable for gene replacement therapy. However, while the origins of disease may vary, there are considerable similarities in the physiological changes that occur in the retina. When early therapeutic intervention is not possible and patients suffer loss of photoreceptor cells but maintain remaining layers of cells in the neural retina, there is an opportunity for a universal gene therapy approach that can be applied regardless of the genetic origin of disease. Optogenetic therapy offers such a strategy by aiming to restore vision though the provision of light-sensitive molecules to surviving cell types of the retina that enable light perception through the residual neurons. Here we review the recent progress in attempts to restore visual function to the degenerate retina using optogenetic therapy. We focus on multiple pre-clinical models used in optogenetic strategies, discuss their strengths and limitations, and highlight considerations including vector and transgene designs that have advanced the field into two ongoing clinical trials.
Highlights
Optogenetics is a method that allows optical control of neural circuitry by ectopic expression of light-sensitive tools in target cells (Deisseroth et al, 2006)
Both human and mouse retinal cells produce five main opsin variants that respond to different wavelengths of light: rhodopsin, expressed by rod photoreceptor cells (RHO); short-wave cone opsin (SWC), medium-wave cone opsin (MWC), and long-wave cone opsin (LWC), expressed by cone photoreceptor cells; and melanopsin (OPN4)
The pre-clinical work to date demonstrates that optogenetic strategies are able to restore vision to the degenerate retina using a multitude of transgene and vector combinations
Summary
Optogenetics is a method that allows optical control of neural circuitry by ectopic expression of light-sensitive tools in target cells (Deisseroth et al, 2006). In a degenerate retina that has lost the light-sensitive photoreceptor cells, optogenetic therapy is a promising approach that combines neurobiology and genetic engineering techniques to provide light-mediated control over the cell physiology in surviving retinal cells that are normally insensitive to light. Adeno-associated viral (AAV) vector-based delivery of a transgene encoding light-sensitive protein, channelrhodopsin (ChR2), was shown to be targeted to surviving cells of the retina, whereby its ectopic expression in cellular membranes converted the. Optogenetic Retinal Gene Therapy cells into artificial photoreceptors (Bi et al, 2006; Sahel and Roska, 2013) This landmark study highlighted several important challenges that needed to be addressed before optogenetics could be considered for human studies. Stimulation via external artificial light source would be necessary for this strategy to work as human therapy, but such high radiation levels are potentially toxic to the retina. The work reviewed highlight the great progress achieved in the field to date, which has led to two ongoing clinical trials with further upcoming human trials trials likely in the near future
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