Gene therapy to cure botulinum toxin intoxication and new motoneuron delivery system (2007-2009)

The aim of the project is to establish two biotechnological strategies to help curing motoneuronal diseases. Botulinum neurotoxins (BoNTs) are the deadliest toxins known. They provoke profound flaccid neuromuscular paralysis that leads to death due to respiratory failure. There are no current therapies available and affected patients require respiratory assistance for up to 7 months with sophisticated respirators. BoNT is therefore an acquired motoneuronal disease and a well-known biological weapon which is also easy to produce in large quantities. It is therefore important to provide a quick and efficient way of overriding BoNT-induced paralysis other than very costly mechanical respirators. Our first strategy aims at designing a gene therapy against botulism. BoNTs promote muscular paralysis by cleaving molecules implicated in the mechanism of neuronal communication (SNARE proteins). Our aim is to deliver genetically modified uncleavable forms of SNAREs to rescue neuronal communication and prevent botulism. BoNT are comprised of two chains: a toxic light chain and a non toxic heavy chain which is responsible for the extreme selectivity of BoNT for motoneurons and for delivering the light chain in the motoneuronal cytosol by a mechanism named translocation. Our second aim is to use the BoNTs atoxic heavy chain to engineer a selective motoneuronal delivery system. This could be useful in the future to deliver molecules of interest in diseased motoneurons.