A systematic comparison of optogenetic approaches to visual restoration

Gilhooley, Michael James; Lindner, Moritz; Palumaa, Teele; Hughes, Steven; Peirson, Stuart N.; Hankins, Mark W.

doi:10.1016/j.omtm.2022.03.003

Cited by 16 publications

(18 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Immunostaining of retina sections was performed as described previously (Gilhooley et al, 2022; Hughes et al, 2013). Visualization of ReaChR-mCitrine was enhanced using a chicken polyclonal anti-GFP antibody diluted 1:1000 that also recognizes mCitrine (GFP-1020, AVES labs).…”

Section: Methodsmentioning

confidence: 99%

Functional integrity of visual coding following advanced photoreceptor degeneration

Rodgers

Hughes

Lindner

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Photoreceptor degeneration sufficient to produce severe visual loss often spares the inner retina. This raises the hope that treatments using optogenetics or electrical stimulation, which generate a replacement light input signal in surviving neurons, may restore vision. The success of these approaches is dependent on the capacity of surviving circuits in the early stages of the visual system to generate and propagate an appropriate visual code in the face of neuroanatomical remodelling. To determine the capacity of surviving circuits in advanced retinal degeneration to present an appropriate visual code, we generated a transgenic mouse expressing the optogenetic actuator ReaChR in ON bipolar cells (second order neurons in the visual projection). After crossing this with the rd1 model of photoreceptor degeneration, we compared ReaChR derived responses with photoreceptor-driven responses in wildtype (WT) mice in retinal ganglion cells and visual thalamus. The ReaChR-driven responses in rd1 animals showed low photosensitivity, but in other respects generated a visual code that was very similar to WT. Furthermore, ReaChR rd1 units in the retina had high response reproducibility and showed sensitivity normalisation to code contrast stably across different background intensities. At the single unit level, ReaChR-derived responses exhibited broadly similar variation in light response polarity, contrast sensitivity and temporal frequency tuning as WT. Units from WT and ReaChR rd1 mice clustered together when subjected to unsupervised community detection based on stimulus-response properties. Our data reveal an impressive ability for surviving circuitry to recreate a rich visual code following advanced retinal degeneration and are promising for regenerative medicine in the central nervous system.

show abstract

Section: Methodsmentioning

confidence: 99%

Functional integrity of visual coding following advanced photoreceptor degeneration

Rodgers

Hughes

Lindner

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…A wider spectral range of neuronal activity modulators and voltage sensors together with improved optics will increase the scope for (all)-optical electrophysiological characterization of neural circuitry, also lending insight into neuronal function (and dysfunction) in the brain ( Villette et al, 2019 ; Guimarães Backhaus et al, 2021 ; Sharma et al, 2021 ; Zou et al, 2021 ; Prakash et al, 2022 ; Sridharan et al, 2022 ; Tan et al, 2022 ). Other important medical targets may also arise using optogenetics to correct physiological defects and address pathological conditions, where first steps have already been taken ( Braun et al, 1995 ; Deubner et al, 2019 ; Shen et al, 2020 ; Acharya et al, 2021 ; Cokic et al, 2021 ; Kathe et al, 2021 ; Gilhooley et al, 2022 ; Sun et al, 2022 ).…”

Section: Prospectsmentioning

confidence: 99%

Rhodopsins: An Excitingly Versatile Protein Species for Research, Development and Creative Engineering

Grip

Ganapathy

2022

Front. Chem.

View full text Add to dashboard Cite

The first member and eponym of the rhodopsin family was identified in the 1930s as the visual pigment of the rod photoreceptor cell in the animal retina. It was found to be a membrane protein, owing its photosensitivity to the presence of a covalently bound chromophoric group. This group, derived from vitamin A, was appropriately dubbed retinal. In the 1970s a microbial counterpart of this species was discovered in an archaeon, being a membrane protein also harbouring retinal as a chromophore, and named bacteriorhodopsin. Since their discovery a photogenic panorama unfolded, where up to date new members and subspecies with a variety of light-driven functionality have been added to this family. The animal branch, meanwhile categorized as type-2 rhodopsins, turned out to form a large subclass in the superfamily of G protein-coupled receptors and are essential to multiple elements of light-dependent animal sensory physiology. The microbial branch, the type-1 rhodopsins, largely function as light-driven ion pumps or channels, but also contain sensory-active and enzyme-sustaining subspecies. In this review we will follow the development of this exciting membrane protein panorama in a representative number of highlights and will present a prospect of their extraordinary future potential.

show abstract

“…An important issue is the extent to which we can expect functional benefits from bipolar-targeted versus downstream RCG-targeted therapy. Some studies have described the advantages of bipolar-targeted therapy [ 23 , 24 ], but the opposite result has also been reported [ 25 ]. Verification of the theoretical priority provided by preserving retinal processing would be the key to developing bipolar cell-targeted optogenetic therapy.…”

Section: Strategies and Target Cellsmentioning

confidence: 99%

“…Tyrosine-mutated AAVs are generated through rational mutagenesis to improve intracellular nuclear trafficking, based on the finding that phosphorylation of surface-exposed tyrosine residues on AAV leads to ubiquitination and subsequent proteasome-mediated degradation. Intravitreal injection of AAV2 quadruple mutants (Y272, 444, 500, 730F; 4YF) has been demonstrated to transduce bipolar cells using either the Grm6 [ 16 , 20 , 72 ] or L7-5 promoter [ 24 , 51 ] in rodent models. When AAV2(4YF) was used with the hSyn-1 promoter, optogenetic gene expression was dominant in RGCs [ 70 ].…”

Section: Gene Deliverymentioning

confidence: 99%

Optogenetic Therapy for Visual Restoration

Sakai

Tomita

Maeda

2022

IJMS

View full text Add to dashboard Cite

Optogenetics is a recent breakthrough in neuroscience, and one of the most promising applications is the treatment of retinal degenerative diseases. Multiple clinical trials are currently ongoing, less than a decade after the first attempt at visual restoration using optogenetics. Optogenetic therapy has great value in providing hope for visual restoration in late-stage retinal degeneration, regardless of the genotype. This alternative gene therapy consists of multiple elements including the choice of target retinal cells, optogenetic tools, and gene delivery systems. Currently, there are various options for each element, all of which have been developed as a product of technological success. In particular, the performance of optogenetic tools in terms of light and wavelength sensitivity have been improved by engineering microbial opsins and applying human opsins. To provide better post-treatment vision, the optimal choice of optogenetic tools and effective gene delivery to retinal cells is necessary. In this review, we provide an overview of the advancements in optogenetic therapy for visual restoration, focusing on available options for optogenetic tools and gene delivery methods.

show abstract

A systematic comparison of optogenetic approaches to visual restoration

Cited by 16 publications

References 84 publications

Functional integrity of visual coding following advanced photoreceptor degeneration

Functional integrity of visual coding following advanced photoreceptor degeneration

Rhodopsins: An Excitingly Versatile Protein Species for Research, Development and Creative Engineering

Optogenetic Therapy for Visual Restoration

Contact Info

Product

Resources

About