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

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          Abstract

          As the technological hurdles are overcome and optogenetic techniques advance to have more control over neurons, therapies based on these approaches will begin to emerge in the clinic. Here, we consider the technical challenges surrounding the transition of this breakthrough technology from an investigative tool to a true therapeutic avenue. The emerging strategies and remaining tasks surrounding genetically encoded molecules which respond to light as well as the vehicles required to deliver them are discussed.The use of optogenetics in humans would represent a completely new paradigm in medicine and would be associated with unprecedented technical considerations. To be applied for stimulation of neurons in humans, an ideal optogenetic tool would need to be non-immunogenic, highly sensitive, and activatable with red light or near-infrared light (to maximize light penetration while minimizing photodamage). To enable sophisticated levels of neuronal control, the combined use of optogenetic actuators and indicators could enable closed-loop all-optical neuromodulation. Such systems would introduce additional challenges related to spectral orthogonality between actuator and indicator, the need for decision making computational algorithms and requirements for large gene cassettes. As in any gene therapy, the therapeutic efficiency of optogenetics will rely on vector delivery and expression in the appropriate cell type. Although viral vectors such as those based on AAVs are showing great potential in human trials, barriers to their general use remain, including immune responses, delivery/transport, and liver clearance. Limitations associated with the gene cassette size which can be packaged in currently approved vectors also need to be addressed.

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          Most cited references75

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          Neocortical excitation/inhibition balance in information processing and social dysfunction.

          Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.
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            Emerging Issues in AAV-Mediated In Vivo Gene Therapy

            In recent years, the number of clinical trials in which adeno-associated virus (AAV) vectors have been used for in vivo gene transfer has steadily increased. The excellent safety profile, together with the high efficiency of transduction of a broad range of target tissues, has established AAV vectors as the platform of choice for in vivo gene therapy. Successful application of the AAV technology has also been achieved in the clinic for a variety of conditions, including coagulation disorders, inherited blindness, and neurodegenerative diseases, among others. Clinical translation of novel and effective “therapeutic products” is, however, a long process that involves several cycles of iterations from bench to bedside that are required to address issues encountered during drug development. For the AAV vector gene transfer technology, several hurdles have emerged in both preclinical studies and clinical trials; addressing these issues will allow in the future to expand the scope of AAV gene transfer as a therapeutic modality for a variety of human diseases. In this review, we will give an overview on the biology of AAV vector, discuss the design of AAV-based gene therapy strategies for in vivo applications, and present key achievements and emerging issues in the field. We will use the liver as a model target tissue for gene transfer based on the large amount of data available from preclinical and clinical studies.
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              AAV-Mediated Anterograde Transsynaptic Tagging: Mapping Corticocollicular Input-Defined Neural Pathways for Defense Behaviors.

              To decipher neural circuits underlying brain functions, viral tracers are widely applied to map input and output connectivity of neuronal populations. Despite the successful application of retrograde transsynaptic viruses for identifying presynaptic neurons of transduced neurons, analogous anterograde transsynaptic tools for tagging postsynaptically targeted neurons remain under development. Here, we discovered that adeno-associated viruses (AAV1 and AAV9) exhibit anterograde transsynaptic spread properties. AAV1-Cre from transduced presynaptic neurons effectively and specifically drives Cre-dependent transgene expression in selected postsynaptic neuronal targets, thus allowing axonal tracing and functional manipulations of the latter input-defined neuronal population. Its application in superior colliculus (SC) reveals that SC neuron subpopulations receiving corticocollicular projections from auditory and visual cortex specifically drive flight and freezing, two different types of defense behavior, respectively. Together with an intersectional approach, AAV-mediated anterograde transsynaptic tagging can categorize neurons by their inputs and molecular identity, and allow forward screening of distinct functional neural pathways embedded in complex brain circuits.
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                Author and article information

                Contributors
                Journal
                Front Neural Circuits
                Front Neural Circuits
                Front. Neural Circuits
                Frontiers in Neural Circuits
                Frontiers Media S.A.
                1662-5110
                15 July 2020
                2020
                : 14
                : 41
                Affiliations
                [1] 1Department of Chemistry, University of Alberta , Edmonton, AB, Canada
                [2] 2Department of Chemistry, Graduate School of Science, The University of Tokyo , Tokyo, Japan
                [3] 3Centre de Recherche CERVO, Université Laval , Quebec City, QC, Canada
                [4] 4Département de Physique et Génie Physique, Université Laval , Quebec City, QC, Canada
                [5] 5Département de Biochimie, Microbiologie et Bioinformatique, Université Laval , Quebec City, QC, Canada
                Author notes

                Edited by: Jean-Claude Béïque, University of Ottawa, Canada

                Reviewed by: Daniel Llano, University of Illinois at Urbana-Champaign, United States; Anna Beyeler, Institut National de la Santé et de la Recherche Médicale (INSERM), France

                *Correspondence: Marie-Eve Paquet marie-eve.paquet@ 123456bcm.ulaval.ca
                Article
                10.3389/fncir.2020.00041
                7373823
                32760252
                3dac37e6-7de0-4d90-b97f-b8186e69104c
                Copyright © 2020 Shen, Campbell, Côté and Paquet.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 13 March 2020
                : 16 June 2020
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 96, Pages: 11, Words: 9148
                Categories
                Neuroscience
                Mini Review

                Neurosciences
                optogenetics,viral vectors,therapeutic applications,technical challenges,opsins
                Neurosciences
                optogenetics, viral vectors, therapeutic applications, technical challenges, opsins

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