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Re-Assembled Botulinum Neurotoxin Inhibits CNS Functions without Systemic Toxicity

Author(s): Enrico Ferrari | Elizabeth S. Maywood | Laura Restani | Matteo Caleo | Marco Pirazzini | Ornella Rossetto | Michael H. Hastings | Dhevahi Niranjan | Giampietro Schiavo | Bazbek Davletov

Journal: Toxins ISSN 2072-6651
Volume: 3; Issue: 4; Start page: 345; Date: 2011;
Original page

Keywords: botulinum neurotoxin | nervous system | protein engineering | synapse | SNAREs | BOTOX | BITOX

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.