Article

LiGluR Restores Visual Responses in Rodent Models of Inherited Blindness

Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720-2020, USA.
Molecular Therapy (Impact Factor: 6.23). 05/2011; 19(7):1212-9. DOI: 10.1038/mt.2011.103
Source: PubMed

ABSTRACT

Inherited retinal degeneration results from many different mutations in either photoreceptor-specific or nonphotoreceptor-specific genes. However, nearly all mutations lead to a common blinding phenotype that initiates with rod cell death, followed by loss of cones. In most retinal degenerations, other retinal neuron cell types survive for long periods after blindness from photoreceptor loss. One strategy to restore light responsiveness to a retina rendered blind by photoreceptor degeneration is to express light-regulated ion channels or transporters in surviving retinal neurons. Recent experiments in rodents have restored light-sensitivity by expressing melanopsin or microbial opsins either broadly throughout the retina or selectively in the inner segments of surviving cones or in bipolar cells. Here, we present an approach whereby a genetically and chemically engineered light-gated ionotropic glutamate receptor (LiGluR) is expressed selectively in retinal ganglion cells (RGCs), the longest-surviving cells in retinal blinding diseases. When expressed in the RGCs of a well-established model of retinal degeneration, the rd1 mouse, LiGluR restores light sensitivity to the RGCs, reinstates light responsiveness to the primary visual cortex, and restores both the pupillary reflex and a natural light-avoidance behavior.

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    • "In this situation, functionalized AuNPs similar to those used in the present study could be injected into the eye where they would bind to the RGCs, allowing light entering the eye to directly excite the RGCs and thus bypass the inoperative photoreceptors. The critical importance of achieving vision repair in photoreceptor degenerative diseases is motivating approaches that currently include opto-electronic , optogenetic, pharmacological, and other strategies to engineer light sensitivity of RGCs or other retinal neurons (Bharti et al., 2014; Bi et al., 2006; Caporale et al., 2011; Chader et al., 2009; Greenberg et al., 2011; Lagali et al., 2008; Polosukhina et al., 2012; Theogarajan, 2012). "
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    • "LiGluRs can be delivered to the retina using AAVs and confer transduced cells sensitive to the light-switchable photochromic ligand. This approach was able to restore the light sensitivity of RGCs in a mouse model retinitis pigmentosa[158]. "
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