Citation

Ferrari E, Maywood ES, Restani L, Caleo M, Pirazzini M, Rossetto O, Hastings MH, Niranjan D, Schiavo G, Davletov B. Toxins (Basel) 2011; 3(4): 345-355.

Affiliation

Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK; Email: eferrari@mrc-lmb.cam.ac.uk (E.F.); emaywood@mrc-lmb.cam.ac.uk (E.S.M.); mha@mrc-lmb.cam.ac.uk (M.H.H.); niranjan@mrc-lmb.cam.ac.uk (D.N.).

Copyright

(Copyright © 2011, MDPI: Multidisciplinary Digital Publishing Institute)

DOI

10.3390/toxins3040345

PMID

22069712

PMCID

PMC3202830

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.

Language: en