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

Re-Assembled Botulinum Neurotoxin Inhibits CNS Functions without Systemic Toxicity

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1 Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK 2 Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, 56100 Pisa, Italy 3 Dipartimento di Scienze Biomediche, Università di Padova, 35121 Padova, Italy 4 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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Abstract

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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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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