Channelrhodopsin-2 gene transduced into retinal ganglion cells restores functional vision in genetically blind rats

Tomita, Hiroshi; Sugano, Eriko; Isago, Hiroaki; Hiroi, Teru; Wang, Zhuo; Ohta, Emi; Tamai, Makoto

doi:10.1016/j.exer.2009.12.006

Cited by 128 publications

(93 citation statements)

References 46 publications

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“…We have been studying light-gated cation-selective membrane channel protein channelrhodopsin-2 (ChR2) 3 to induce photoreceptor function in retinal neurons such as RGCs 4,5 and ON bipolar cells. 6 We have already demonstrated that the responses induced by various stimulus frequencies (Hz) in ChR2-transduced rats are in no way inferior to those in normal rats, 7 as supported by the finding that ChR2-induced photocurrents are extremely fast. 8,9 Visual function was also well analysed by using transgenic rats with ChR2 transduction into RGCs: the spatial frequencies based on behavioural responses of photoreceptordegenerated ChR2 transgenic rats were the same as those of normal rats.…”

Section: Introductionmentioning

confidence: 79%

Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy

et al. 2010

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We had previously reported that transduction of the channelrhodopsin-2 (ChR2) gene into retinal ganglion cells restores visual function in genetically blind, dystrophic Royal College of Surgeons (RCS) rats. In this study, we attempted to reveal the safety and influence of exogenous ChR2 gene expression. Adeno-associated virus (AAV) type 2 encoding ChR2 fused to Venus (rAAV-ChR2V) was administered by intra-vitreous injection to dystrophic RCS rats. However, rAAV-ChR2 gene expression was detected in non-target organs (intestine, lung and heart) in some cases. ChR2 function, monitored by recording visually evoked potentials, was stable across the observation period (64 weeks). No change in retinal histology and no inflammatory marker of leucocyte adhesion in the retinal vasculature were observed. Although antibodies to rAAV (0.01-12.21 mg ml À1 ) and ChR2 (0-4.77 mg ml À1 ) were detected, their levels were too low for rejection. T-lymphocyte analysis revealed recognition by T cells and a transient inflammation-like immune reaction only until 1 month after the rAAV-ChR2V injection. In conclusion, ChR2, which originates from Chlamydomonas reinhardtii, can be expressed without immunologically harmful reactions in vivo. These findings will help studies of ChR2 gene transfer to restore vision in progressed retinitis pigmentosa.

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Section: Introductionmentioning

confidence: 79%

Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy

et al. 2010

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“…23 Similar treatments were shown to evoke changes in behavior in rat models of RP. 43,44 Furthermore, blind transgenic mice 45 and rats 46 have been generated that express ChR2 only in a subset of ganglion cells. The retinas of these transgenic animals regained light sensitivity and the rats showed visually guided behavior.…”

Section: Strategies For Optogenetic Restoration Of Visionmentioning

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 As an alternative to retinal prosthesis, optogenetics can be used to restore vision by expressing optical neuromodulators such as channelrhodopsins or photochemically modified mammalian ion channels in residual retinal neurons. [7][8][9][10][11][12][13][14][15] Expression of channelrhodopsin in RGCs might allow greater spatial resolution and acuity than that achieved with current prosthetic devices. This has motivated a large body of proof-of-concept studies in rodents and other small animals, which have shown the feasibility of the approach, [7][8][9][10][16][17][18] and a first-in-human phase 1 clinical trial was initiated recently (ClinicalTrials.gov NCT02556736).…”

Section: Introductionmentioning

confidence: 99%

A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina

et al. 2017

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The majority of inherited retinal degenerations converge on the phenotype of photoreceptor cell death. Second-and third-order neurons are spared in these diseases, making it possible to restore retinal light responses using optogenetics. Viral expression of channelrhodopsin in the third-order neurons under ubiquitous promoters was previously shown to restore visual function, albeit at light intensities above illumination safety thresholds. Here, we report (to our knowledge, for the first time) activation of macaque retinas, up to 6 months post-injection, using channelrhodopsin-Ca 2+ -permeable channelrhodopsin (CatCh) at safe light intensities. High-level CatCh expression was achieved due to a new promoter based on the regulatory region of the gamma-synuclein gene (SNCG) allowing strong expression in ganglion cells across species. Our promoter, in combination with clinically proven adeno-associated virus 2 (AAV2), provides CatCh expression in peri-foveolar ganglion cells responding robustly to light under the illumination safety thresholds for the human eye. On the contrary, the threshold of activation and the proportion of unresponsive cells were much higher when a ubiquitous promoter (cytomegalovirus [CMV]) was used to express CatCh. The results of our study suggest that the inclusion of optimized promoters is key in the path to clinical translation of optogenetics.

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Channelrhodopsin-2 gene transduced into retinal ganglion cells restores functional vision in genetically blind rats

Cited by 128 publications

References 46 publications

Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy

Immune responses to adeno-associated virus type 2 encoding channelrhodopsin-2 in a genetically blind rat model for gene therapy

Optogenetic therapy for retinitis pigmentosa

A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina

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