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


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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Available from: Dirk Trauner, Oct 04, 2015
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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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    ABSTRACT: Unmodified neurons can be directly stimulated with light to produce action potentials, but such techniques have lacked localization of the delivered light energy. Here we show that gold nanoparticles can be conjugated to high-avidity ligands for a variety of cellular targets. Once bound to a neuron, these particles transduce millisecond pulses of light into heat, which changes membrane capacitance, depolarizing the cell and eliciting action potentials. Compared to non-functionalized nanoparticles, ligand-conjugated nanoparticles highly resist convective washout and enable photothermal stimulation with lower delivered energy and resulting temperature increase. Ligands targeting three different membrane proteins were tested; all showed similar activity and washout resistance. This suggests that many types of ligands can be bound to nanoparticles, preserving ligand and nanoparticle function, and that many different cell phenotypes can be targeted by appropriate choice of ligand. The findings have applications as an alternative to optogenetics and potentially for therapies involving neuronal photostimulation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 03/2015; DOI:10.1016/j.neuron.2015.02.033 · 15.05 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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    ABSTRACT: Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are blinding diseases caused by the degeneration of rods and cones, leaving the remainder of the visual system unable to respond to light. Here, we report a chemical photoswitch named DENAQ that restores retinal responses to white light of intensity similar to ordinary daylight. A single intraocular injection of DENAQ photosensitizes the blind retina for days, restoring electrophysiological and behavioral responses with no toxicity. Experiments on mouse strains with functional, nonfunctional, or degenerated rods and cones show that DENAQ is effective only in retinas with degenerated photoreceptors. DENAQ confers light sensitivity on a hyperpolarization-activated inward current that is enhanced in degenerated retina, enabling optical control of retinal ganglion cell firing. The acceptable light sensitivity, favorable spectral sensitivity, and selective targeting to diseased tissue make DENAQ a prime drug candidate for vision restoration in patients with end-stage RP and AMD.
    Neuron 02/2014; 81(4):800-13. DOI:10.1016/j.neuron.2014.01.003 · 15.05 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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    ABSTRACT: Mouse models are useful tools for developing potential therapies for human inherited retinal diseases, such as retinitis pigmentosa (RP), since more strains are being identified with the same mutant genes and phenotypes as humans with corresponding retinal degenerative diseases. Mutations in the beta subunit of the human rod phosphodiesterase (PDE6B) gene are a common cause of autosomal recessive RP (arRP). This article focuses on two well-established naturally occurring mouse models of arRP caused by spontaneous mutations in Pde6b, their discovery, phenotype, mechanism of degeneration, strengths and limitations, and therapeutic approaches to restore vision and delay disease progression. Viral vector, especially adeno-associated viral vector (AAV) -mediated gene replacement therapy, pharmacological treatment, cell-based therapy and other approaches that extend the therapeutic window of treatment, is a potentially promising strategy for improving photoreceptor function and significantly slowing the process of retinal degeneration.
    Molecular vision 12/2013; 19:2579-2589. · 1.99 Impact Factor
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