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: 6.43). 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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    Neuron 03/2015; DOI:10.1016/j.neuron.2015.02.033 · 15.98 Impact Factor
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    • "Transplantation of stem cell-derived photoreceptors can restore retinal light responses to blind mice (Lamba et al., 2009), and a retinal pigment epithelium transplant has improved vision in a patient with AMD (Schwartz et al., 2012). Viral expression of microbial opsins (Busskamp et al., 2010; Lagali et al., 2008; Thyagarajan et al., 2010) or other optogenetic tools (Caporale et al., 2011) can restore visual responses in blind mouse models of RP. All of these strategies have shown promise for restoring visual function, but they are either invasive (i.e., implantation of electronic chips) or irreversible (i.e., transplantation of photoreceptor progenitors or viral expression of optogenetic tools). "
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    Neuron 02/2014; 81(4):800-13. DOI:10.1016/j.neuron.2014.01.003 · 15.98 Impact Factor
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    • "ChR2 gene delivery in ON bipolar cells was also achieved, leading to restored photosensitivity and behavioral responses in animal models [80,81]. Caporale et al. used an AAV2-mediated intravitreal delivery of an engineered light-gated ionotropic glutamate receptor to restore light responsiveness to the retinal ganglion cells of adult rd1 mice [82]. "
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