Abstract
Botulinum neurotoxin (BoNT) is a major therapeutic agent that is licensed in neurological indications, such as dystonia and spasticity. The BoNT family, which is produced in nature by clostridial bacteria, comprises several pharmacologically distinct proteins with distinct properties. In this review, we present an overview of the current therapeutic landscape and explore the diversity of BoNT proteins as future therapeutics. In recent years, novel indications have emerged in the fields of pain, migraine, overactive bladder, osteoarthritis, and wound healing. The study of biological effects distal to the injection site could provide future opportunities for disease-tailored BoNT therapies. However, there are some challenges in the pharmaceutical development of BoNTs, such as liquid and slow-release BoNT formulations; and, transdermal, transurothelial, and transepithelial delivery. Innovative approaches in the areas of formulation and delivery, together with highly sensitive analytical tools, will be key for the success of next generation BoNT clinical products.
Highlights
Botulinum neurotoxin (BoNT) is a major therapeutic agent that is licensed in neurological indications, such as dystonia and spasticity
Clinical evidence highlighted the effect of BoNT/A on nerve growth factor (NGF) release, as well as TRPV1 expression, which are involved in the development of detrusor overactivity [86,87]
compound muscle action potential (CMAP) amplitude and/or cleaved SNAP25 immunohistochemistry in remote muscles, support the dose dependent systemic spread effect in rats that were injected with BoNT/A [116,117]
Summary
Based upon the use of neutralising antibodies, there are currently seven different serotypes of botulinum neurotoxin (BoNT) that have been reported, from BoNT A through to G. BoNT/B showed to be less potent in the clinic than had been anticipated based on its efficacy during animal studies The reason for this has recently been identified as a residue difference within human synaptotagmin II, which is the protein receptor for BoNT/B [3,4]. All of the commercially available BoNT products are manufactured using native Clostridium botulinum as the production organism, some companies are exploring the use of recombinant expression using Escherichia coli. This would allow a standardised and safer manufacturing process for BoNT/A and for other serotypes and genetically modified versions of the neurotoxin
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