Double-Binding Botulinum Molecule with Reduced Muscle Paralysis: Evaluation in In Vitro and In Vivo Models of Migraine
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ORIGINAL ARTICLE
Double-Binding Botulinum Molecule with Reduced Muscle Paralysis: Evaluation in In Vitro and In Vivo Models of Migraine Anna P. Andreou 1,2 & Charlotte Leese 3 & Rosaria Greco 4 & Chiara Demartini 4,5 & Eve Corrie 3 & Deniz Simsek 3 & Anna Zanaboni 4,5 & Ksenia Koroleva 6 & Joseph O. Lloyd 1 & Giorgio Lambru 1,2 & Ciara Doran 3 & Oleg Gafurov 6 & Elizabeth Seward 3 & Rashid Giniatullin 6,7 & Cristina Tassorelli 4,5 & Bazbek Davletov 3 Accepted: 4 November 2020 # The Author(s) 2020
Abstract With a prevalence of 15%, migraine is the most common neurological disorder and among the most disabling diseases, taking into account years lived with disability. Current oral medications for migraine show variable effects and are frequently associated with intolerable side effects, leading to the dissatisfaction of both patients and doctors. Injectable therapeutics, which include calcitonin gene–related peptide–targeting monoclonal antibodies and botulinum neurotoxin A (BoNT/A), provide a new paradigm for treatment of chronic migraine but are effective only in approximately 50% of subjects. Here, we investigated a novel engineered botulinum molecule with markedly reduced muscle paralyzing properties which could be beneficial for the treatment of migraine. This stapled botulinum molecule with duplicated binding domain—binary toxin-AA (BiTox/AA)—cleaves synaptosomal-associated protein 25 with a similar efficacy to BoNT/A in neurons; however, the paralyzing effect of BiTox/ AA was 100 times less when compared to native BoNT/A following muscle injection. The performance of BiTox/AA was evaluated in cellular and animal models of migraine. BiTox/AA inhibited electrical nerve fiber activity in rat meningeal preparations while, in the trigeminovascular model, BiTox/AA raised electrical and mechanical stimulation thresholds in Aδ- and Cfiber nociceptors. In the rat glyceryl trinitrate (GTN) model, BiTox/AA proved effective in inhibiting GTN-induced hyperalgesia in the orofacial formalin test. We conclude that the engineered botulinum molecule provides a useful prototype for designing advanced future therapeutics for an improved efficacy in the treatment of migraine. Key Words Migraine . botulinum . trigeminal . trigeminovascular . glyceryl trinitrate model . multivalent . neuronal delivery Anna P. Andreou, Charlotte Leese and Rosaria Greco contributed equally to this work. * Bazbek Davletov [email protected] 1
Headache Research-Wolfson Centre for Age-Related Diseases, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
2
Headache Centre, Guy’s and St Thomas’s NHS Foundation Trust, King’s Health Partners, London, UK
3
Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, UK
4
Translational Neurovascular Research Unit, IRCCS Mondino Foundation, Pavia, Italy
5
Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
6
Laboratory of Neurobiology, Kazan University, Kazan, Russia
7
A.I. Virtanen Institute for Molecular Sci
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