Re-engineering clostridial neurotoxins for the treatment of chronic pain: current status and future prospects.
Clostridial neurotoxins from the botulinum neurotoxin (BoNT) family are protein complexes, derived from the bacterium Clostridium botulinum, which potently inhibit acetylcholine release and result in a reversible blockade of the neuromuscular junction. This feature led to the clinical development of BoNT-A for a number of neuromuscular disorders. BoNT-A toxins are commercially available as three different preparations: Dysport/Azzalure, Botox/Vistabel, and Xeomin/Bocouture. Although BoNT-A preparations have not yet been approved for the treatment of pain, a substantial body of preclinical and clinical evidence shows that BoNT-A is effective in treating a number of different types of pain. It is thought to exert an analgesic effect both via muscle-relaxant properties and also directly, via inhibition of nociceptive neuropeptides. This review explores the mechanistic basis of this analgesic effect, summarizing current knowledge of the structure-function relationship of BoNT and discussing effects on both motor and pain neurons. For a complete picture of the analgesic properties of BoNT-A, clinical evidence of efficacy in myofascial pain and neuropathic pain is considered in tandem with a mechanistic rationale for activity. Patients experiencing chronic pain are clear candidates for treatment with a modified clostridial endopeptidase that would provide enduring inhibition of neurotransmitter release. A strong preclinical evidence base underpins the concept that re-engineering of BoNT could be used to enhance the analgesic potential of this neurotoxin, and it is hoped that the first clinical studies examining re-engineered BoNT-A will confirm this potential.
Pickett
Andy
A
Biologicals Science and Technology, Ipsen Biopharm Limited, Wrexham, UK. andy.pickett@ipsen.com
D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001905:Botulinum Toxins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D019274:Botulinum Toxins, Type A / Q000494:pharmacology / Q000627:therapeutic use; D002908:Chronic Disease; D006801:Humans; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010146:Pain / Q000145:classification / Q000188:drug therapy*; D015202:Protein Engineering; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
D000700:Analgesics; D009498:Neurotoxins; D001905:Botulinum Toxins; D019274:Botulinum Toxins, Type A