Optogenetic Retinal Gene Therapy with the Light Gated GPCR Vertebrate Rhodopsin

Gaub, Benjamin M.; Berry, Michael; Visel, Meike; Holt, Amy; Isacoff, Ehud Y.; Flannery, John G.

doi:10.1007/978-1-4939-7522-8_12

Cited by 15 publications

(11 citation statements)

References 20 publications

(28 reference statements)

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“…Such probes may also be advantageous for advanced BMI systems that require precise stimulation and minimal interference between signals. However, few optogenetic genes have been identified and cleared for use in humans due to safety concerns [137138]. Genetic engineering remains quite challenging due to its unknown long-term impact on humans, although it is expected that these technologies will be utilized in various BMI systems once issues regarding safety and stability have been addressed.…”

Section: Multi-modal Neural Probes To Measure Both Electrical and Optmentioning

confidence: 99%

Implantable Neural Probes for Brain-Machine Interfaces ? Current Developments and Future Prospects

et al. 2018

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A Brain-Machine interface (BMI) allows for direct communication between the brain and machines. Neural probes for recording neural signals are among the essential components of a BMI system. In this report, we review research regarding implantable neural probes and their applications to BMIs. We first discuss conventional neural probes such as the tetrode, Utah array, Michigan probe, and electroencephalography (ECoG), following which we cover advancements in next-generation neural probes. These next-generation probes are associated with improvements in electrical properties, mechanical durability, biocompatibility, and offer a high degree of freedom in practical settings. Specifically, we focus on three key topics: (1) novel implantable neural probes that decrease the level of invasiveness without sacrificing performance, (2) multi-modal neural probes that measure both electrical and optical signals, (3) and neural probes developed using advanced materials. Because safety and precision are critical for practical applications of BMI systems, future studies should aim to enhance these properties when developing next-generation neural probes.

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Section: Multi-modal Neural Probes To Measure Both Electrical and Optmentioning

confidence: 99%

Implantable Neural Probes for Brain-Machine Interfaces ? Current Developments and Future Prospects

et al. 2018

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“…An alternative approach is to endow light sensitivity to downstream neurons of the inner retina that survive following photoreceptor loss 6 , 7 , either with synthetic photoswitches, which actuate native ion channels 8 – 12 , or by genetic introduction of a light-sensitive signaling protein. A number of light-sensitive signaling proteins have been tested, including two microbial opsins, the ion channel channelrhodopsin and ion pump halorhodopsin 13 – 18 , chemically engineered mammalian receptors 19 , 20 and two G-protein coupled receptor (GPCR) opsins that are native to the retina, rhodopsin of rod photoreceptor cells and melanopsin of intrinsically photosensitive retinal ganglion cells 21 – 25 . These light-gated systems, when delivered to the surviving neurons of the blind retina using adeno-associated viruses (AAVs), restore light sensitivity, transmission of light-driven activity to higher order visual centers in the brain, and both innate and learned visually guided behaviors.…”

Section: Introductionmentioning

confidence: 99%

Restoration of high-sensitivity and adapting vision with a cone opsin

et al. 2019

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Inherited and age-related retinal degenerative diseases cause progressive loss of rod and cone photoreceptors, leading to blindness, but spare downstream retinal neurons, which can be targeted for optogenetic therapy. However, optogenetic approaches have been limited by either low light sensitivity or slow kinetics, and lack adaptation to changes in ambient light, and not been shown to restore object vision. We find that the vertebrate medium wavelength cone opsin (MW-opsin) overcomes these limitations and supports vision in dim light. MW-opsin enables an otherwise blind retinitis pigmenotosa mouse to discriminate temporal and spatial light patterns displayed on a standard LCD computer tablet, displays adaption to changes in ambient light, and restores open-field novel object exploration under incidental room light. By contrast, rhodopsin, which is similar in sensitivity but slower in light response and has greater rundown, fails these tests. Thus, MW-opsin provides the speed, sensitivity and adaptation needed to restore patterned vision.

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“…The efficient expression of intravitreally-injected viral vector, combined with high photosensitivity of expressed MCO1 mitigates the hitherto faced challenges in optogenetics vision restoration like the use of high intensity light source and or active stimulation device. Use of vertebrate rhodopsin presents an important avenue for use as optogenetic tools for treatment of retinal disorders with photoreceptor degeneration [42]. However, vertebrate rhodopsin, used ectopically to control G-coupled signaling in cultured cells, has greater rundown with repeated stimulation and deactivates slowly upon switching off the light stimulation [43].…”

Section: Discussionmentioning

confidence: 99%

Sensitization of ON-bipolar cells with ambient light activatable multi-characteristic opsin rescues vision in mice

Batabyal¹,

Gajjeraman²,

Pradhan³

et al. 2020

Gene Ther

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Gene therapy-based treatment such as optogenetics offers a potentially powerful way to bypass damaged photoreceptors in retinal degenerative diseases and use the remaining retinal cells for functionalization to achieve photosensitivity. However, current approaches of optogenetic treatment rely on opsins that require high intensity light for activation thus adding to the challenge for use as part of a wearable device. Here, we report AAV2 assisted delivery of highly photosensitive multicharacteristic opsin (MCO1) into ON-bipolar cells of mice with retinal degeneration to allow activation by ambient light. Rigorous characterization of delivery efficacy by different doses of AAV2 carrying MCO1 (vMCO1) into targeted cells showed durable expression over 6 months after delivery as measured by reporter expression. The enduring MCO1 expression was correlated with the significantly improved behavioral outcome, that was longitudinally measured by visual water-maze and optomotor assays. The pro/anti-inflammatory cytokine levels in plasma and vitreous humor of the vMCO1injected group did not change significantly from baseline or control group. Furthermore, biodistribution studies at various time points after injection in animal groups injected with different doses of vMCO1 showed non-detectable vector copies in non-targeted tissues. Immunohistochemistry of vMCO1 transfected retinal tissues showed bipolar specific expression of MCO1 and the absence of immune/inflammatory response. Furthermore, ocular imaging using SD-OCT showed no change in the structural architecture of vMCO1-injected eyes. Induction of ambient light responsiveness to remaining healthy bipolar cells in subjects with retinal degeneration will allow the retinal circuitry to gain visual acuity without requiring an active stimulation device.

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Optogenetic Retinal Gene Therapy with the Light Gated GPCR Vertebrate Rhodopsin

Cited by 15 publications

References 20 publications

Implantable Neural Probes for Brain-Machine Interfaces ? Current Developments and Future Prospects

Implantable Neural Probes for Brain-Machine Interfaces ? Current Developments and Future Prospects

Restoration of high-sensitivity and adapting vision with a cone opsin

Sensitization of ON-bipolar cells with ambient light activatable multi-characteristic opsin rescues vision in mice

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