Restoration of visual function in retinal degeneration mice by ectopic expression of melanopsin

Lin, Bin; Koizumi, Amane; Tanaka, Nobushige; Panda, Satchidananda; Masland, Richard H.

doi:10.1073/pnas.0806114105

Cited by 266 publications

(252 citation statements)

References 26 publications

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“…The brightest light stimulus we used was 2 × 10 16 photons·cm −2 ·s −1 during pupillometry (however, significant differences between groups were seen at lower intensities) or ≈13,000 lx (Table S3) equivalent to daylight conditions. The brighter stimulus intensity used for pupillometry in our experiments compared with previous studies using melanopsin likely reflects the use of different animal models (37) and our use of a 2-s white light stimulus (chosen to be a more useful stimulus for imageforming vision), whereas other studies used monochromatic light (37) and longer stimulus durations more suited for activating ipRGCs (5). The quality of vision that might be restored by OPN4 gene therapy is likely to be affected by its response kinetics.…”

Section: Visual Responses Requiring Image-forming Vision Are Generatedmentioning

confidence: 56%

“…Previous work used intravitreal delivery of an adeno-associated viral (AAV) vector to express mouse melanopsin in ganglion cells with restoration of visual responses (5). We investigated whether human melanopsin (OPN4) could be effectively delivered via an alternative subretinal approach, using a ubiquitous (CBA) promoter to drive expression in all remaining outer retinal cells for several reasons.…”

mentioning

confidence: 99%

“…An alternative gene therapy strategy involves the expression of transgenes encoding photosensitive proteins in remaining retinal cells, making them directly light sensitive in the absence of rods and cones (3)(4)(5)(6)(7). A candidate protein for this purpose is melanopsin, the photopigment naturally present in a subset of ganglion cells that are intrinsically photosensitive [intrinsically photosensitive retinal ganglion cells (ipRGCs)] (8).…”

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confidence: 99%

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Long-term restoration of visual function in end-stage retinal degeneration using subretinal human melanopsin gene therapy

Silva

Barnard

Hughes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Optogenetic strategies to restore vision in patients who are blind from end-stage retinal degenerations aim to render remaining retinal cells light sensitive once photoreceptors are lost. Here, we assessed long-term functional outcomes following subretinal delivery of the human melanopsin gene (OPN4) in the rd1 mouse model of retinal degeneration using an adeno-associated viral vector. Ectopic expression of OPN4 using a ubiquitous promoter resulted in cellular depolarization and ganglion cell action potential firing. Restoration of the pupil light reflex, behavioral light avoidance, and the ability to perform a task requiring basic image recognition were restored up to 13 mo following injection. These data suggest that melanopsin gene therapy via a subretinal route may be a viable and stable therapeutic option for the treatment of endstage retinal degeneration in humans.human melanopsin | gene therapy | optogenetics

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Section: Visual Responses Requiring Image-forming Vision Are Generatedmentioning

confidence: 56%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Long-term restoration of visual function in end-stage retinal degeneration using subretinal human melanopsin gene therapy

Silva

Barnard

Hughes

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…If the slow kinetics of melanopsin-induced responses could be engineered to be faster, this tool could be highly valuable for immunological reasons. 63 The use of AAV-2 has been shown to be safe for human patients. 64 However, the more potent serotypes, for example, AAV-7 and AAV-8, have not yet been tested in the clinic.…”

Section: Immune Responsesmentioning

confidence: 99%

Optogenetic therapy for retinitis pigmentosa

et al. 2011

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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.

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“…6−11,13−15 Another light-sensitive class of proteins that has also been cloned and expressed heterologously is melanopsin, a photoisomerizable pigment that signals through the G protein of the G q family in a specialized subset of retinal ganglion cells. 12 Other groups have employed synthetic chemistry approaches that avoid expression of foreign proteins. For example, some groups have synthesized photolabile "caged" neurotransmitters that liberate the neurotransmitter upon photolysis by UV illumination, 16,17 thereby enabling light to activate ligand-gated ion channels.…”

mentioning

confidence: 99%

Light-Triggered Modulation of Cellular Electrical Activity by Ruthenium Diimine Nanoswitches

Rohan

Citron

Durrell³

et al. 2013

ACS Chem. Neurosci.

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Ruthenium diimine complexes have previously been used to facilitate light-activated electron transfer in the study of redox metalloproteins. Excitation at 488 nm leads to a photoexcited state, in which the complex can either accept or donate an electron, respectively, in the presence of a soluble sacrificial reductant or oxidant. Here, we describe a novel application of these complexes in mediating light-induced changes in cellular electrical activity. We demonstrate that RubpyC17 ([Ru(bpy) 2 (bpy-C17)] 2+ , where bpy is 2,2′-bipyridine and bpy-C17 is 2,2′-4-heptadecyl-4′-methyl-bipyridine), readily incorporates into the plasma membrane of cells, as evidenced by membrane-confined luminescence. Excitable cells incubated in RubpyC17 and then illuminated at 488 nm in the presence of the reductant ascorbate undergo membrane depolarization leading to firing of action potentials. In contrast, the same experiment performed with the oxidant ferricyanide, instead of ascorbate, leads to hyperpolarization. These experiments suggest that illumination of membrane-associated RubpyC17 in the presence of ascorbate alters the cell membrane potential by increasing the negative charge on the outer face of the cell membrane capacitor, effectively depolarizing the cell membrane. We rule out two alternative explanations for light-induced membrane potential changes, using patch clamp experiments: (1) lightinduced direct interaction of RubpyC17 with ion channels and (2) light-induced membrane perforation. We show that incorporation of RubpyC17 into the plasma membrane of neuroendocrine cells enables light-induced secretion as monitored by amperometry. While the present work is focused on ruthenium diimine complexes, the findings point more generally to broader application of other transition metal complexes to mediate light-induced biological changes.

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Restoration of visual function in retinal degeneration mice by ectopic expression of melanopsin

Cited by 266 publications

References 26 publications

Long-term restoration of visual function in end-stage retinal degeneration using subretinal human melanopsin gene therapy

Long-term restoration of visual function in end-stage retinal degeneration using subretinal human melanopsin gene therapy

Optogenetic therapy for retinitis pigmentosa

Light-Triggered Modulation of Cellular Electrical Activity by Ruthenium Diimine Nanoswitches

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