Leese, C. orcid.org/0000-0002-3123-0154, Christmas, C. orcid.org/0009-0009-5129-9982, Mészáros, J. orcid.org/0000-0002-8196-9061 et al. (4 more authors) (2023) New botulinum neurotoxin constructs for treatment of chronic pain. Life Science Alliance, 6 (6). e202201631. ISSN 2575-1077
Abstract
Chronic pain affects one in five people across human societies, with few therapeutic options available. Botulinum neurotoxin (BoNT) can provide long-lasting pain relief by inhibiting local release of neuropeptides and neurotransmitters, but its highly paralytic nature has limited its analgesic potential. Recent advances in protein engineering have raised the possibility of synthesising non-paralysing botulinum molecules for translation to pain sufferers. However, the synthesis of these molecules, via several synthetic steps, has been challenging. Here, we describe a simple platform for safe production of botulinum molecules for treating nerve injury–induced pain. We produced two versions of isopeptide-bonded BoNT from separate botulinum parts using an isopeptide bonding system. Although both molecules cleaved their natural substrate, SNAP25, in sensory neurons, the structurally elongated iBoNT did not cause motor deficit in rats. We show that the non-paralytic elongated iBoNT targets specific cutaneous nerve fibres and provides sustained pain relief in a rat nerve injury model. Our results demonstrate that novel botulinum molecules can be produced in a simple and safe manner and be useful for treating neuropathic pain.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2023 Leese et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Rats; Humans; Animals; Chronic Pain; Botulinum Toxins, Type A; Neuralgia; Analgesics; Sensory Receptor Cells |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL MR/K022539/1 Medical Research Council MC_PC_16058 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 26 Apr 2023 13:20 |
Last Modified: | 26 Apr 2023 13:20 |
Status: | Published |
Publisher: | Life Science Alliance, LLC |
Refereed: | Yes |
Identification Number: | 10.26508/lsa.202201631 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:198508 |