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      rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels

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          Abstract

          Chronic pain is common and inadequately treated, making the development of safe and effective analgesics a high priority. Our previous data indicate that carbonic anhydrase-8 (CA8) expression in dorsal root ganglia (DRG) mediates analgesia via inhibition of neuronal ER inositol trisphosphate receptor-1 (ITPR1) via subsequent decrease in ER calcium release and reduction of cytoplasmic free calcium, essential to the regulation of neuronal excitability. This study tested the hypothesis that novel JDNI8 replication-defective herpes simplex-1 viral vectors (rdHSV) carrying a CA8 transgene (vHCA8) reduce primary afferent neuronal excitability. Whole-cell current clamp recordings in small DRG neurons showed that vHCA8 transduction caused prolongation of their afterhyperpolarization (AHP), an essential regulator of neuronal excitability. This AHP prolongation was completely reversed by the specific Kv7 channel inhibitor XE-991. Voltage clamp recordings indicate an effect via Kv7 channels in vHCA8-infected small DRG neurons. These data demonstrate for the first time that vHCA8 produces Kv7 channel activation, which decreases neuronal excitability in nociceptors. This suppression of excitability may translate in vivo as non-opioid dependent behavioral- or clinical analgesia, if proven behaviorally and clinically.

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          Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems

          Ken Chan, Min Jang, Bryan B Yoo … (2017)
          Adeno-associated viruses (AAVs) are commonly used for in vivo gene transfer. Nevertheless, AAVs that provide efficient transduction across specific organs or cell populations are needed. Here, we describe AAV-PHP.eB and AAV-PHP.S, capsids that efficiently transduce the central and peripheral nervous systems, respectively. In the adult mouse, intravenous administration of 1×1011 vector genomes (vg) of AAV-PHP.eB transduced 69% of cortical and 55% of striatal neurons, while 1×1012 vg AAV-PHP.S transduced 82% of dorsal root ganglion neurons, as well as cardiac and enteric neurons. The efficiency of these vectors facilitates robust co-transduction and stochastic, multicolor labeling for individual cell morphology studies. To support such efforts, we provide methods for labeling a tunable fraction of cells without compromising color diversity. Furthermore, when used with cell type-specific promoters, these AAVs provide targeted gene expression across the nervous system and enable efficient and versatile gene manipulation throughout the nervous system of transgenic and non-transgenic animals.
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            Opioids for Chronic Noncancer Pain

            Jason Busse, Li WANG, Mostafa Kamaleldin … (2018)
            Harms and benefits of opioids for chronic noncancer pain remain unclear.
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              Voltage-gated potassium channels as therapeutic targets.

              Heike Wulff, Neil Castle, Luis A. Pardo (2009)
              The human genome encodes 40 voltage-gated K(+) channels (K(V)), which are involved in diverse physiological processes ranging from repolarization of neuronal and cardiac action potentials, to regulating Ca(2+) signalling and cell volume, to driving cellular proliferation and migration. K(V) channels offer tremendous opportunities for the development of new drugs to treat cancer, autoimmune diseases and metabolic, neurological and cardiovascular disorders. This Review discusses pharmacological strategies for targeting K(V) channels with venom peptides, antibodies and small molecules, and highlights recent progress in the preclinical and clinical development of drugs targeting the K(V)1 subfamily, the K(V)7 subfamily (also known as KCNQ), K(V)10.1 (also known as EAG1 and KCNH1) and K(V)11.1 (also known as HERG and KCNH2) channels.
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                Author and article information

                Contributors
                Munal B. Kandel: URI : https://loop.frontiersin.org/people/2678089/overviewRole: Role: Role: Role: Role:
                Gerald Z. Zhuang: Role: Role: Role:
                William F. Goins: URI : https://loop.frontiersin.org/people/1764700/overviewRole: Role: Role: Role: Role: Role: Role:
                Marco Marzulli: Role: Role: Role: Role: Role: Role:
                Mingdi Zhang: Role: Role: Role: Role: Role: Role:
                Joseph C. Glorioso: URI : https://loop.frontiersin.org/people/586719/overviewRole: Role: Role: Role: Role:
                Yuan Kang: URI : https://loop.frontiersin.org/people/2682292/overviewRole: Role: Role:
                Alexandra E. Levitt: Role: Role:
                Wai-Meng Kwok: URI : https://loop.frontiersin.org/people/197048/overviewRole: Role:
                Roy C. Levitt: URI : https://loop.frontiersin.org/people/2320842/overviewRole: Role: Role: Role: Role: Role: Role: Role: Role: Role: Role: Role: Role: Role:
                Konstantinos D. Sarantopoulos: Role: Role: Role: Role: Role: Role: Role: Role: Role: Role: Role: Role: Role:
                Journal
                Journal ID (nlm-ta): Front Mol Neurosci
                Journal ID (iso-abbrev): Front Mol Neurosci
                Journal ID (publisher-id): Front. Mol. Neurosci.
                Title: Frontiers in Molecular Neuroscience
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1662-5099
                Publication date (Electronic): 09 May 2024
                Publication date Collection: 2024
                Volume: 17
                Electronic Location Identifier: 1398839
                Affiliations
                [1] 1Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami Miller School of Medicine , Miami, FL, United States
                [2] 2Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine , Pittsburgh, PA, United States
                [3] 3Bascom Palmer Eye Institute, University of Miami Miller School of Medicine , Miami, FL, United States
                [4] 4Department of Anesthesiology and Department of Pharmacology & Toxicology, Medical College of Wisconsin , Milwaukee, WI, United States
                [5] 5John T. MacDonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine , Miami, FL, United States
                [6] 6John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine , Miami, FL, United States
                Author notes

                Edited by: Mario A. Acuña, University of Bern, Switzerland

                Reviewed by: Ari-Pekka Koivisto, Orion Corporation, Finland

                Fernando Kasanetz, National Scientific and Technical Research Council (CONICET), Argentina

                *Correspondence: Roy C. Levitt, rlevitt@ 123456med.miami.edu

                †Present address: Munal B. Kandel, Department of Neuroscience, University of Connecticut, Farmington, CT, United States

                Article
                DOI: 10.3389/fnmol.2024.1398839
                PMC ID: 11112096
                PubMed ID: 38783904
                SO-VID: ee23cf5f-516e-4e5c-acbc-7695e0ed4d23
                Copyright © Copyright © 2024 Kandel, Zhuang, Goins, Marzulli, Zhang, Glorioso, Kang, Levitt, Kwok, Levitt and Sarantopoulos.
                License:

                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
                Date received : 10 March 2024
                Date accepted : 18 April 2024
                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 81, Pages: 14, Words: 10910
                Funding
                The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was funded in part by NINDS UG3/UH3 NS123964 (RL); NINDS R21 NS105880 (RL); NINDS 3R21NS105880-01S1 (RL); and DoD W81XWH-19-1-0525 (RL).
                Categories
                Subject: Molecular Neuroscience
                Subject: Original Research
                Custom metadata
                section-at-acceptance Pain Mechanisms and Modulators

                ScienceOpen disciplines: Neurosciences
                Keywords: non-opioid analgesia from ca8 gene therapy,carbonic anhydrase-8,kv7 voltage-gated potassium channels,neuronal excitability,afterhyperpolarization,replication defective herpes-1 virus,gene therapy
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: non-opioid analgesia from ca8 gene therapy, carbonic anhydrase-8, kv7 voltage-gated potassium channels, neuronal excitability, afterhyperpolarization, replication defective herpes-1 virus, gene therapy

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