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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Optogenetics is the use of genetic methods combined with optical technology to achieve gain or loss of function within neuronal circuits. The field of optogenetics has been rapidly expanding in efforts to restore visual function to blinding diseases such as retinitis pigmentosa (RP). Most work in the field includes a group of light-sensitive retinaldehyde-binding proteins known as opsins. Opsins couple photon absorption to molecular signaling chains that control cellular ion currents. Targeting of opsin genes to surviving retinal cells is fundamental to the success of optogenetic therapy. Viral delivery, primarily adeno-associated virus, using intravitreal injection for inner retinal cells and subretinal injection for outer retinal cells, has proven successful in many models. Challenges in bioengineering remain for optogenetics including relative insensitivity of opsins to physiologic light levels of stimulation and difficulty with viral delivery in primate models. However, targeting optogenetic therapy may present an even greater challenge. Neural and glial remodeling seen in advanced stages of RP result in reorganization of remaining neural retina, and optogenetic therapy may not yield functional results. Remodeling also poses a challenge to the selection of cellular targets, with bipolar, amacrine and ganglion cells all playing distinct physiologic roles, and affected by remodeling differently. Although optogenetics has drawn closer to clinical utility, advances in opsin engineering, therapeutic targeting and ultimately in molecular inhibition of remodeling will play critical roles in the continued clinical advancement of optogenetic therapy.
    Journal of Ophthalmic & Vision Research 07/2014; 9(3):374-82. DOI:10.4103/2008-322X.143379
  • Source
    [Show abstract] [Hide abstract]
    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 · 15.98 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are progressive retinal diseases that result from the death of rod and cone photoreceptors, ultimately leading to blindness. The only currently approved vision restoration treatment employs an implanted retinal 'chip' as a prosthetic device to electrically stimulate retinal neurons that survive after the photoreceptors are gone, thereby restoring light-driven neural signaling to the brain. Alternative strategies have been proposed, which would utilize optogenetic or optopharmacological tools to enable direct optical stimulation of surviving retinal neurons. Here, we review the latest studies evaluating the feasibility of these molecular tools as potential therapeutics for restoring visual function in human blinding disease. Copyright © 2015. Published by Elsevier Ltd.
    Current Opinion in Neurobiology 02/2015; 34C:74-78. DOI:10.1016/j.conb.2015.01.018 · 6.77 Impact Factor

Full-text (3 Sources)

Available from
May 15, 2014