Date of this Version
Proceedings of the National Academy of Sciences
Most inherited forms of blindness are caused by mutations that lead to photoreceptor cell death but spare second- and third-order retinal neurons. Expression of the light-gated excitatory mammalian ion channel light-gated ionotropic glutamate receptor (LiGluR) in retinal ganglion cells (RGCs) of the retina degeneration (rd1) mouse model of blindness was previously shown to restore some visual functions when stimulated by UV light. Here, we report restored retinal function in visible light in rodent and canine models of blindness through the use of a second-generation photoswitch for LiGluR, maleimide-azobenzene-glutamate 0 with peak efficiency at 460 nm (MAG0460). In the blind rd1 mouse, multielectrode array recordings of retinal explants revealed robust and uniform light-evoked firing when LiGluR-MAG0460 was targeted to RGCs and robust but diverse activity patterns in RGCs when LiGluR-MAG0460 was targeted to ON-bipolar cells (ON-BCs). LiGluR-MAG0460 in either RGCs or ON-BCs of the rd1 mouse reinstated innate light-avoidance behavior and enabled mice to distinguish between different temporal patterns of light in an associative learning task. In the rod-cone dystrophy dog model of blindness, LiGluR-MAG0460 in RGCs restored robust light responses to retinal explants and intravitreal delivery of LiGluR and MAG0460 was well tolerated in vivo. The results in both large and small animal models of photoreceptor degeneration provide a path to clinical translation.
© 2014 National Academy of Sciences.
retinal gene therapy, visual prosthetics, retinitis pigmentosa, optogenetic pharmacology, azobenzene photoswitches
Gaub, B. M., Berry, M. H., Holt, A. E., Reiner, A., Kienzler, M. A., Dolgova, N., Nikonov, S., Aguirre, G. D., Beltran, W. A., Flannery, J. G., & Isacoff, E. Y. (2014). Restoration of Visual Function by Expression of a Light-Gated Mammalian Ion Channel in Retinal Ganglion Cells or ON-Bipolar Cells. Proceedings of the National Academy of Sciences, 111 (51), E5574-E5583. http://dx.doi.org/10.1073/pnas.1414162111
Date Posted: 20 April 2018
This document has been peer reviewed.