Re-assembled botulinum neurotoxin inhibits CNS Functions without systemic toxicity

Ferrari, Enrico and Maywood, Elizabeth S. and Restani, Laura and Caleo, Matteo and Pirazzini, Marco and Rossetto, Ornella and Hastings, Michael H. and Niranjan, Dhevahi and Schiavo, Giampietro and Davletov, Bazbek (2011) Re-assembled botulinum neurotoxin inhibits CNS Functions without systemic toxicity. Toxins, 3 (4). pp. 345-355. ISSN 2072-6651

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Full text URL: http://dx.doi.org/10.3390/toxins3040345

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.

Item Type:Article
Additional Information: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
Subjects:B Subjects allied to Medicine > B140 Neuroscience
C Biological Sciences > C560 Biotechnology
C Biological Sciences > C700 Molecular Biology, Biophysics and Biochemistry
C Biological Sciences > C500 Microbiology
Divisions:College of Science > School of Life Sciences
ID Code:6580
Deposited By: Enrico Ferrari
Deposited On:16 Oct 2012 09:04
Last Modified:26 Nov 2012 22:37

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