Challenges for Therapeutic Applications of Opsin-Based Optogenetic Tools in Humans

Shen, Yi; Campbell, Robert E.; Côté, Daniel; Paquet, Marie‐Eve

doi:10.3389/fncir.2020.00041

Cited by 84 publications

(69 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The use of viral vectors in primates has lagged somewhat behind the progress being made in rodents, but our study is among several to show that widespread, high expression levels can be obtained (Diester et al, 2011, Yazdan-Shahmorad et al, 2016. Optogenetic control of human neurons has been demonstrated in organotypic cultures (Andersson et al, 2016), but more work is needed to assess the potential risks of long-term expression of opsins (Shen et al, 2020). Second, a safe method of delivering sufficient light is required without the infection risk posed by percutaneous light fibres.…”

Section: Discussionmentioning

confidence: 85%

Closed-loop optogenetic control of normal and pathological network dynamics

Zaaimi¹,

Turnbull²,

Hazra³

et al. 2020

Preprint

View full text Add to dashboard Cite

Electrical neurostimulation is effective in treating neurological disorders, but associated recording artefacts generally limit applications to ‘open-loop’ stimuli. Since light does not prevent concurrent electrical recordings, optogenetics enables real-time, continuous ‘closed-loop’ control of brain activity. Here we show that closed-loop optogenetic stimulation with excitatory opsins (CLOSe) affords precise manipulation of neural dynamics, both in vitro, in brain slices from transgenic mice, and in vivo, with anesthetised monkeys. We demonstrate the generation of oscillations in quiescent tissue, enhancement or suppression of endogenous patterns in active tissue, and modulation of seizure-like bursts elicited by 4-aminopyridine. New network properties, emergent under CLOSe, depended on the phase-shift imposed between neural activity and optical stimulation, and could be modelled with a nonlinear dynamical system. In particular, CLOSe could stabilise or destabilise limit cycles associated with seizure oscillations, evident from systematic changes in the variability and entropy of seizure trajectories that correlated with their altered duration and intensity. Furthermore, CLOSe was achieved using intracortical optrodes incorporating light-emitting diodes, paving the way for translation of closed-loop optogenetics towards therapeutic applications in humans.

show abstract

Section: Discussionmentioning

confidence: 85%

Closed-loop optogenetic control of normal and pathological network dynamics

Zaaimi¹,

Turnbull²,

Hazra³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…This meant that the stimulating site must be close to the body surface; otherwise, we were not able to achieve effective expression efficiency. As optogenetic techniques had developed, many optimized systems have become available that are activated by near-infrared light or red light [ 12 , 27 ]. Near-infrared light and red light are considered to be ideal sources of stimulation due to their higher penetration and reduced risk of photodamage.…”

Section: Discussionmentioning

confidence: 99%

Temporal induction of Lhx8 by optogenetic control system for efficient bone regeneration

Huang

Ren

et al. 2021

Stem Cell Res Ther

View full text Add to dashboard Cite

Background The spatiotemporal regulation of essential genes is crucial for controlling the growth and differentiation of cells in a precise manner during regeneration. Recently, optogenetics was considered as a potent technology for sophisticated regulation of target genes, which might be a promising tool for regenerative medicine. In this study, we used an optogenetic control system to precisely regulate the expression of Lhx8 to promote efficient bone regeneration. Methods Quantitative real-time PCR and western blotting were used to detect the expression of Lhx8 and osteogenic marker genes. Alkaline phosphatase staining and alizarin red staining were used to detect alkaline phosphatase activity and calcium nodules. A customized optogenetic expression system was constructed to regulate Lhx8, of which the expression was activated in blue light but not in dark. We also used a critical calvarial defect model for the analysis of bone regeneration in vivo. Moreover, micro-computed tomography (micro-CT), three-dimensional reconstruction, quantitative bone measurement, and histological and immunohistochemistry analysis were performed to investigate the formation of new bone in vivo. Results During the osteogenic differentiation of BMSCs, the expression levels of Lhx8 increased initially but then decreased thereafter. Lhx8 promoted the early proliferation of BMSCs but inhibited subsequent osteogenic differentiation. The optogenetic activation of Lhx8 in BMSCs in the early stages of differentiation by blue light stimulation led to a significant increase in cell proliferation, thus allowing a sufficient number of differentiating BMSCs to enter the later osteogenic differentiation stage. Analysis of the critical calvarial defect model revealed that the pulsed optogenetic activation of Lhx8 in transplanted BMSCs over a 5-day period led to a significant increase in the generation of bone in vivo. Conclusions Lhx8 plays a critical role in balancing proliferation and osteogenic differentiation in BMSCs. The optogenetic activation of Lhx8 expression at early stage of BMSCs differentiation led to better osteogenesis, which would be a promising strategy for precise bone regeneration.

show abstract

“…But our promising therapies still face relevant challenges. In this sense, CRISP/Cas editing tools used to amend genetic missenses, need to fix secondary effects, as those related to the immune response (Yu et al, 2017); stem cell approaches have to procure the functionality of transplanted cells in the recipient, to assure the accurate establishment of synaptic connectivity and cell contacts, and gain success in precise image processing (Cuevas et al, 2019;Garita-Hernandez et al, 2019); and optogenetics also needs to find appropriate vectors for the delivery and expression in suitable cell types, avoiding immunological rejection of the vector systems (Shen et al, 2020). While gene-and cell-based therapies evolve through the tortuous pathway of biological success, combined therapies with antioxidant (as lutein or zeaxanthin), antiinflammatory (as corticosteroids or cannabinoids), and antiapoptotic (as tauroursodeoxycholic acid or proinsulin) molecules appear currently as the widest approach to pharmacologically treat a wide spectrum of retinal degenerative diseases.…”

Section: Current and Future Therapeutic Strategies For The Treatment Of Retinal Neurodegenerative Diseasesmentioning

confidence: 99%

Current and future therapeutic strategies for the treatment of retinal neurodegenerative diseases

2022

View full text Add to dashboard Cite

Challenges for Therapeutic Applications of Opsin-Based Optogenetic Tools in Humans

Cited by 84 publications

References 99 publications

Closed-loop optogenetic control of normal and pathological network dynamics

Closed-loop optogenetic control of normal and pathological network dynamics

Temporal induction of Lhx8 by optogenetic control system for efficient bone regeneration

Current and future therapeutic strategies for the treatment of retinal neurodegenerative diseases

Contact Info

Product

Resources

About