Optogenetic therapy for retinitis pigmentosa

Abstract

Retinitis pigmentosa (RP) refers to a diverse group of progressive, hereditary diseases of the retina that lead to incurable blindness and affect two million people worldwide. Artificial photoreceptors constructed by gene delivery of light-activated channels or pumps ('optogenetic tools') to surviving cell types in the remaining retinal circuit has been shown to restore photosensitivity in animal models of RP at the level of the retina and cortex as well as behaviorally. The translational potential of this optogenetic approach has been evaluated using in vitro studies involving post-mortem human retinas. Here, we review recent developments in this expanding field and discuss the potential and limitations of optogenetic engineering for the treatment of RP.

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

“…Furthermore, RGCs are easily targeted due to their proximity to the vitreous, enabling strong, uniform, and widespread expression after intravitreal injection of AAV vectors. ON-BCs, however, are promising therapeutic targets for early-stage disease because they are located upstream in the retinal circuit and provide an opportunity to preserve aspects of retinal processing (32,33).…”

“…Ideally, a visual prosthetic should have low variability, elicit RGC firing similar to wild-type (wt) conditions, and show fast dynamics to restore natural vision after loss of photoreceptor cells (31)(32)(33). LiGluR-MAG0 460 expressed in ON-BC and RGC showed low cell-to-cell variability (Fig.…”

Gene Therapy of Inherited Retinopathies: A Long and Successful Road from Viral Vectors to Patients

“…The recent discovery of EPO mutants that lack erythropoietic activity while retaining neuronal protective effects (Leist et al, 2004) has allowed the successful testing of AAV-mediated intraocular delivery of these derivatives in IR animal models (Colella et al, 2011;Sullivan et al, 2011). Another strategy that is independent of the mutation underlying the disease relies on gene delivery of light-activated ion channels or pumps to retinal neurons (either PRs, bipolar, or ganglion cells) to stimulate retinal activity (Busskamp et al, 2012). As this optogenetic strategy has the potential to render light-sensitive cells that are normally not, it can be applied to end-stage retinal diseases in which PRs are lost at the time of intervention.…”

“…As this optogenetic strategy has the potential to render light-sensitive cells that are normally not, it can be applied to end-stage retinal diseases in which PRs are lost at the time of intervention. So far, AAVmediated delivery of microbial opsins (channelrhodopsin-2 and halorhodopsin) or of the light-gated ionotropic glutamate receptor (LiGluR) restored light sensitivity in various murine models of IRs and human postmortem retinas (Busskamp et al, 2012).…”

Ocular gene therapy: introduction to the special issue

“…An alternative approach that has been reviewed in this special issue is the use of optogenetics to target genetically encoded light sensors to the cells in the remaining retinal circuitry, thus converting these cells into artificial photoreceptors. 9 If the artificial photoreceptors are connected to other cell types in the retinal circuit, light would also modulate the activity of these cells. The current challenges lie in choosing the right sensor and targeting strategy, so that the light-evoked retinal activity arising from artificial photoreceptors will be similar to the activity of normal retinas stimulated through normal photoreceptors.…”