Botulism is a severe and potentially fatal disease characterized by muscle paralysis. The causing agent, botulinum neurotoxins (BoNTs), can enter motor neurons and block neurotransmission. While rare, botulism is potentially fatal. The nerve-damaging botulinum neurotoxins produced by Clostridium botulinum are one the most potent toxins known. Members of BoNTs such as BoNT/A exhibit extremely long half-life within neurons, resulting in persistent paralysis for months, yet no therapeutics can inhibit BoNTs once they enter neurons.
Researchers at the Boston Children’s Hospital created nontoxic botulinum that could be used for drug delivery.
The toxin-based delivery platform consists of the modified botulinum toxin and the nanobody (the active drug). When this nanobody-toxin fusion protein binds to the receptor on the neuron surface, the cell takes it in through the process of endocytosis, corralling the fusion protein inside a vesicle. The toxin's protease domain, carrying the nanobody, then crosses into the interior of the cell.
Dong, et al. found that the nanobody administration in mice shortened the duration of local muscle paralysis, restoring muscle function within hours, and rescued mice from systemic toxicity of lethal doses of BoNT/A. The fusion of two nanobodies, one against BoNT/A and the other against BoNT/B, created a multivalent therapeutic protein able to neutralize both BoNT/A and BoNT/B in mice. Opening up the door for intracellular delivery of therapeutics targeting cytosolic proteins and processes.
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