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New botulinum neurotoxin constructs for treatment of chronic pain

Leese, Charlotte; Christmas, Claire; Mészáros, Judit; Ward, Stephanie; Maiaru, Maria; Hunt, Stephen P; Davletov, Bazbek; (2023) New botulinum neurotoxin constructs for treatment of chronic pain. Life Science Alliance , 6 (6) , Article e202201631. 10.26508/lsa.202201631. Green open access

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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.

Type: Article
Title: New botulinum neurotoxin constructs for treatment of chronic pain
Open access status: An open access version is available from UCL Discovery
DOI: 10.26508/lsa.202201631
Publisher version: https://doi.org/10.26508/lsa.202201631
Language: English
Additional information: © 2023 Leese et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10169493
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