Journal Article

Restoration of visual function by expression of a light-gated mammalian ion channel in retinal ganglion cells or ON-bipolar cells

Berry, Michael H., Reiner, Andreas, Kienzler, Michael A., Gaub, Benjamin M., Nikonov, Sergei, Holt, Amy E., Aguirre, Gustavo D., Beltran, William A., Dolgova, Natalia, Isacoff, Ehud Y., Flannery, John G.

2014

Overview

We restored visual function to animal models of human blindness using a chemical compound that photosensitizes a mammalian ion channel. Virus-mediated expression of this light sensor in surviving retinal cells of blind mice restored light responses in vitro, reanimated innate light avoidance, and enabled learned visually guided behavior. The treatment also restored light responses to the retina of blind dogs. Patients that might benefit from this treatment would need to have intact ganglion cell and nerve fiber layers. In general, these are patients diagnosed with retinitis pigmentosa and some forms of Leber congenital amaurosis. Patients diagnosed with other types of blindness, for example, age-related macular degeneration or diabetic retinopathy, would not be candidates for this treatment. 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 (MAG0 460 ). In the blind rd1 mouse, multielectrode array recordings of retinal explants revealed robust and uniform light-evoked firing when LiGluR-MAG0 460 was targeted to RGCs and robust but diverse activity patterns in RGCs when LiGluR-MAG0 460 was targeted to ON-bipolar cells (ON-BCs). LiGluR-MAG0 460 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-MAG0 460 in RGCs restored robust light responses to retinal explants and intravitreal delivery of LiGluR and MAG0 460 was well tolerated in vivo. The results in both large and small animal models of photoreceptor degeneration provide a path to clinical translation.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animal models / Animals / Apoptosis / Biological Sciences / blindness / Blindness - physiopathology / Cells / diabetic retinopathy / dogs / Dystrophy / ganglia / humans / Ion Channel Gating / ion channels / Ion Channels - physiology / Ion Channels - radiation effects / Light / macular degeneration / Mammals / Mice / Mice, Inbred C3H / Mice, Inbred C57BL / nerve fibers / Neurons / patients / PNAS Plus / PNAS Plus Significance Statements / Retina / Retinal Ganglion Cells - physiology / Retinal Ganglion Cells - radiation effects / Rodents / Ultraviolet radiation / Vision, Ocular