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Toxins 2011, 3(4), 345-355; doi:10.3390/toxins3040345

Re-Assembled Botulinum Neurotoxin Inhibits CNS Functions without Systemic Toxicity

Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK
Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, 56100 Pisa, Italy
Dipartimento di Scienze Biomediche, Università di Padova, 35121 Padova, Italy
Molecular NeuroPathoBiology Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, UK
Author to whom correspondence should be addressed.
Received: 24 February 2011 / Revised: 18 March 2011 / Accepted: 23 March 2011 / Published: 24 March 2011
(This article belongs to the Special Issue Development of Botulinum Toxin Drugs)
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The therapeutic potential of botulinum neurotoxin type A (BoNT/A) has recently been widely recognized. BoNT/A acts to silence synaptic transmission via specific proteolytic cleavage of an essential neuronal protein, SNAP25. The advantages of BoNT/A-mediated synaptic silencing include very long duration, high potency and localized action. However, there is a fear of possible side-effects of BoNT/A due to its diffusible nature which may lead to neuromuscular blockade away from the injection site. We recently developed a “protein-stapling” technology which allows re-assembly of BoNT/A from two separate fragments. This technology allowed, for the first time, safe production of this popular neuronal silencing agent. Here we evaluated the re-assembled toxin in several CNS assays and assessed its systemic effects in an animal model. Our results show that the re-assembled toxin is potent in inhibiting CNS function at 1 nM concentration but surprisingly does not exhibit systemic toxicity after intraperitoneal injection even at 200 ng/kg dose. This shows that the re-assembled toxin represents a uniquely safe tool for neuroscience research and future medical applications.
Keywords: botulinum neurotoxin; nervous system; protein engineering; synapse; SNAREs; BOTOX; BITOX botulinum neurotoxin; nervous system; protein engineering; synapse; SNAREs; BOTOX; BITOX

This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Ferrari, E.; Maywood, E.S.; Restani, L.; Caleo, M.; Pirazzini, M.; Rossetto, O.; Hastings, M.H.; Niranjan, D.; Schiavo, G.; Davletov, B. Re-Assembled Botulinum Neurotoxin Inhibits CNS Functions without Systemic Toxicity. Toxins 2011, 3, 345-355.

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