Precision spinal gene delivery-induced functional switch in nociceptive neurons reverses neuropathic pain.

Animals Gene Transfer Techniques Mice Neuralgia / etiology Nociceptors Posterior Horn Cells Spinal Cord Spinal Cord Dorsal Horn Swine
GAD65 and VGAT long-lasting pain reversal neuropathic pain precision spinal vector delivery subpial injection technique subpial non-human primates subpial pig targeted AAV9 delivery

Journal

Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581

Informations de publication

Date de publication:
03 08 2022
Historique:
received: 12 01 2022
revised: 31 03 2022
accepted: 29 04 2022
pubmed: 8 5 2022
medline: 9 8 2022
entrez: 7 5 2022
Statut: ppublish

Résumé

Second-order spinal cord excitatory neurons play a key role in spinal processing and transmission of pain signals to the brain. Exogenously induced change in developmentally imprinted excitatory neurotransmitter phenotypes of these neurons to inhibitory has not yet been achieved. Here, we use a subpial dorsal horn-targeted delivery of AAV (adeno-associated virus) vector(s) encoding GABA (gamma-aminobutyric acid) synthesizing-releasing inhibitory machinery in mice with neuropathic pain. Treated animals showed a progressive and complete reversal of neuropathic pain (tactile and brush-evoked pain behavior) that persisted for a minimum of 2.5 months post-treatment. The mechanism of this treatment effect results from the switch of excitatory to preferential inhibitory neurotransmitter phenotype in dorsal horn nociceptive neurons and a resulting increase in inhibitory activity in regional spinal circuitry after peripheral nociceptive stimulation. No detectable side effects (e.g., sedation, motor weakness, loss of normal sensation) were seen between 2 and 13 months post-treatment in naive adult mice, pigs, and non-human primates. The use of this treatment approach may represent a potent and safe treatment modality in patients suffering from spinal cord or peripheral nerve injury-induced neuropathic pain.

Identifiants

DOI: 10.1016/j.ymthe.2022.04.023 PMID: 35524407 PMC: PMC9372322
pubmed: 35524407
pii: S1525-0016(22)00294-5
doi: 10.1016/j.ymthe.2022.04.023
pmc: PMC9372322
pii:
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

2722-2745

Subventions

Organisme : NINDS NIH HHS
ID : R01 NS113189
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS123160
Pays : United States

Informations de copyright

Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests M.M. is a co-founder of Neurgain Technologies.

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Auteurs

Takahiro Tadokoro (T)

Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego (UCSD), La Jolla, CA 92037, USA; Department of Anesthesiology, University of Ryukyus, Okinawa, Japan; Neurgain Technologies, 9620 Towne Centre Drive, Suite 100, San Diego, CA 92121, USA.

Mariana Bravo-Hernandez (M)

Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.

Kirill Agashkov (K)

Departments of Sensory Signaling and Molecular Biophysics, Bogomoletz Institute of Physiology, Kyiv, Ukraine.

Yoshiomi Kobayashi (Y)

Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.

Oleksandr Platoshyn (O)

Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.

Michael Navarro (M)

Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.

Silvia Marsala (S)

Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego (UCSD), La Jolla, CA 92037, USA; Neurgain Technologies, 9620 Towne Centre Drive, Suite 100, San Diego, CA 92121, USA.

Atsushi Miyanohara (A)

Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego (UCSD), La Jolla, CA 92037, USA; Vector Core Laboratory, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.

Tetsuya Yoshizumi (T)

Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.

Michiko Shigyo (M)

Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.

Volodymyr Krotov (V)

Departments of Sensory Signaling and Molecular Biophysics, Bogomoletz Institute of Physiology, Kyiv, Ukraine.

Stefan Juhas (S)

Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Rumburská 89, 277 21 Liběchov, Czech Republic.

Jana Juhasova (J)

Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Rumburská 89, 277 21 Liběchov, Czech Republic.

Duong Nguyen (D)

Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Rumburská 89, 277 21 Liběchov, Czech Republic.

Helena Kupcova Skalnikova (H)

Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Rumburská 89, 277 21 Liběchov, Czech Republic.

Jan Motlik (J)

Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Rumburská 89, 277 21 Liběchov, Czech Republic.

Hana Studenovska (H)

Institute of Macromolecular Chemistry, Czech Academy of Sciences, Department of Biomaterials and Bioanalogous Systems, Heyrovsky Square 2,162 06 Prague 6, Czech Republic.

Vladimir Proks (V)

Institute of Macromolecular Chemistry, Czech Academy of Sciences, Department of Biomaterials and Bioanalogous Systems, Heyrovsky Square 2,162 06 Prague 6, Czech Republic.

Rajiv Reddy (R)

Department of Anesthesiology, Pain Medicine, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.

Shawn P Driscoll (SP)

Gene Expression Laboratory and the Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Thomas D Glenn (TD)

Gene Expression Laboratory and the Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Taratorn Kemthong (T)

National Primate Research Center of Thailand, Chulalongkorn University, Kaengkhoi District, Saraburi 18110, Thailand.

Suchinda Malaivijitnond (S)

National Primate Research Center of Thailand, Chulalongkorn University, Kaengkhoi District, Saraburi 18110, Thailand.

Zoltan Tomori (Z)

Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, Kosice, Slovakia.

Ivo Vanicky (I)

Institute of Neurobiology, Biomedical Research Center, Slovak Academy of Sciences, Kosice, Slovakia.

Manabu Kakinohana (M)

Department of Anesthesiology, University of Ryukyus, Okinawa, Japan.

Samuel L Pfaff (SL)

Gene Expression Laboratory and the Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Joseph Ciacci (J)

Department of Neurosurgery, University of California, San Diego (UCSD), La Jolla, CA 92037, USA.

Pavel Belan (P)

Departments of Sensory Signaling and Molecular Biophysics, Bogomoletz Institute of Physiology, Kyiv, Ukraine; Kyiv Academic University, Kyiv, Ukraine.

Martin Marsala (M)

Neuroregeneration Laboratory, Department of Anesthesiology, University of California, San Diego (UCSD), La Jolla, CA 92037, USA; Institute of Neurobiology, Biomedical Research Center, Slovak Academy of Sciences, Kosice, Slovakia. Electronic address: mmarsala@ucsd.edu.

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Classifications MeSH

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