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

Abstract

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 lightevoked 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 rodcone 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.retinal gene therapy | visual prosthetics | retinitis pigmentosa | optogenetic pharmacology | azobenzene photoswitches

Pulse trains to percepts: the challenge of creating a perceptually intelligible world with sight recovery technologies

“…Although optogenetics and small molecule photoswitches can be targeted with varying degrees of cell specificity (e.g. to cones [44], ganglion cells [4,5,7,[12][13][14], bipolar ON cells [7,13,15], and even ganglion cell dendrites and soma [45]), none of the rstb.royalsocietypublishing.org Phil. Trans.…”

“…If inserted into a subset of remaining retinal cells, they have the potential to make these cells light sensitive [4]. Small molecule photoswitch compounds create novel light responses via small molecules that directly modulate the activity of ion channels by reversibly activating and deactivating the targeted channel with exposure to particular wavelengths of light [5][6][7]. Retinal and cortical prostheses directly elicit neural responses using electrical stimulation, analogous to a cochlear implant (e.g.…”

A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina

“…6 As an alternative to retinal prosthesis, optogenetics can be used to restore vision by expressing optical neuromodulators such as channelrhodopsins or photochemically modified mammalian ion channels in residual retinal neurons. [7][8][9][10][11][12][13][14][15] Expression of channelrhodopsin in RGCs might allow greater spatial resolution and acuity than that achieved with current prosthetic devices. This has motivated a large body of proof-of-concept studies in rodents and other small animals, which have shown the feasibility of the approach, [7][8][9][10][16][17][18] and a first-in-human phase 1 clinical trial was initiated recently (ClinicalTrials.gov NCT02556736).…”

Optogenetic user s guide to Opto-GPCRs

“…Several red-shifted PTLs have been engineered (Figure 3), with one variant (MAG 460 ) that is activated by blue light (460 nm). MAG 460 has the further advantage to spontaneously relax back to the inactive trans-state, making inactivation by a second wavelength superfluous (30). Recently, toCl-MAG, a variant activated by even longer wavelengths (yellow and red light) was developed.…”