Inherited retinal diseases (IRDs) affect 1 in 3000-4000 individuals globally and is now believed to be the major cause of blindness in developed countries. The FDA approvals of the Argus® II electronic retinal implant in 2013 and the Luxturna® gene-replacement therapy in 2017 have sparked hope for patients with IRDs. Unfortunately, the former has been discontinued due to various reasons including medical complications, while the latter is only eligible to 1 in 100,000 – 2 millions patients with recessive RPE65-linked Leber's congenital amaurosis and genetic correction needs to be performed early in the disease before development of vision-impairing pathology. With over 300 genetic mutations implicated in IRDs, there is a clear need for the development of causative gene-agnostic therapeutic approaches. Optogenetics represents one such approach that has been ardently investigated over the last decade.
Optogenetics for vision restoration involves delivering light-sensing opsins to naturally non-light sensitive inner retinal neurons that remain intact in IRDs to render them light-sensitive, as a means to replace lost or dysfunctional photoreceptors that cause irreversible blindness. There are two major classes of opsins commonly investigated in the field: Type I (microbial) and Type II (mammalian) opsins. Preclinical studies in animal models involving both types of opsins have suggested that optogenetics may restore vision in blind animals. Our preclinical study exploring bReaChES, a red-shifted Type I channelrhodopsin has further suggested vision restoration at ecologically relevant light levels. bReaChES-expressing retinal ganglion cells demonstrate spectral and temporal response characteristics approaching those of normal human photopic vision. The PIONEER phase I/IIa clinical trial that involves delivery of channelrhodopsin, ChrimsonR to retinal ganglion cells, paired with light-stimulating goggles, has reported partial recovery of vision in a blind patient with advanced retinitis pigmentosa.
There is confidence that optogenetics holds promise for restoring vision in IRDs even in late disease stages, but important areas, such as the most ideal candidate, most efficient vector or promoter for gene delivery and expression, and chronic immunogenicity, remain to be investigated to overcome translational challenges.