Botulinum neurotoxins development

Clostridium botulinum neurotoxin, the most effective toxin known to date, with a mice lethal dose of about 50 pg/mL (330 fmol/mL) was the target antigen in IPCR assays developed by Wu et al. [48] and Chao et al. [88]. In these assays, detection limits of 5 fg (33 amol) and 50 fg (330 amol), respectively, were found. 

Schmidt, J.J. and Stafford, R.G. 2005. Botulinum neurotoxin serotype F identification of substrate recognition requirements and development of inhibitors with low nanomolar affinity. Biochemistry 44 4067 073. 

Adler, Oyler, Keller, and Lebeda provide an overview of botulinum neurotoxin action leading into a description of the syndrome known as botulism and a discussion of possible treatment options. Subsequently, Adler et al. develop purported terrorist or military anticipated use of botulinum neurotoxin and the threat thereof. This threat of use has led to investments in research that have achieved several major milestones... 

Schmidt, J.J., Stafford, R.G., and Bostian, K. A., Type A botulinum neurotoxin proteolytic activity Development of competitive inhibitors and implication for substrate specificity at the SR binding site, FEES Lett, 435, 61, 1998. 

Pang, Y.P., Vummenthala, A., Mishra, R.K., Park, J.G., Wang, S., Davis, J., Millard, C.B., and Schmidt, J.J. (2009) Potent new small-molecule inhibitor of botulinum neurotoxin serotype A endopeptidase developed by synthesis-based computer-aided molecular design. PLoS One, 4, e7730. 

A 62-year-old woman with Parkinson disease received botulinum neurotoxin (BoNT) injections to treat painful spasticity in her hands. She developed severe generalised dystonia shortly after BoNT injections [30]. 

Botulinum neurotoxin (BoNT) is the most potent poison known to mankind. Currently no antidote is available to rescue poisoned synapses. An effective medical countermeasure strategy would require developing a drug that could rescue poisoned neuromuscular synapses and include its efficient delivery specifically to poisonedpresynaptic nerve terminals. Here we report a drug delivery strategy that could directly deliver toxin inhibitors into the intoxicated nerve terminal cytosol. 

A targeted delivery vehicle was developed for intracellular transport of emerging botulinum neurotoxin antagonists. The drug delivery vehicle consisted of... 

Therefore, we developed a drug delivery vehicle (DDV) comprising the nontoxic recombinant heavy chain of BoNT-A coupled to a 10-kDa amino dextran via the heterobifunctional linker 3-(2-pyridylthio)-propionyl hydrazide. The heavy chain served to target botulinum neurotoxin-sensitive cells and promote internalization of the complex, while the dextran served as a platform to deliver model therapeutic molecules to the targeted cells. 

WH, Clark M, Hartz S, Adler M Development of a delivery vehicle for intracellular transport of botulinum neurotoxin antagonists. 2002,... 

Recently, a novel approach for the detection of Clostridium botulinum neurotoxins was developed (Ogert et al., 1992). This technique involved a two-step sandwich immunoassay utilizing an evanescent wave of light to excite fiuorescently labeled antibodies bound to type A toxin captured on the surface of antibody immobilized fibers. Despite the many... 

Wound botulism occurs where C. botulinum spores germinate in wound infections and develop into vegetative cells. In such cases, neurotoxin is produced which leads to the onset of neurological symptoms. According to the Centers for Disease Control and Prevention, 23 cases of wound botulism (13.6% of all botulism cases) were reported in 2001 in the U.S. Wound botulism has also been diagnosed after intravenous drug injection (Rundervoort et al., 2003). 

Sakaguchi G (1982) Clostridium botulinum toxins. Pharmacol Ther 19 165-94 Sankhla C, Jankovic J, Duane D (1998) Variability of the immunologic and clinical response in dystonic patients immunoresistant to botulinum toxin injections. Mov Disord 13 150-54 Schantz EJ, Johnson EA (1997) Botulinum toxin the story of its development for the treatment of human disease. Perspect Biol Med 40 317-27 Schiavo G (2006) Structural biology dangerous liaisons on neurons. Nature 444 1019-20 Schiavo G, Matteoli M, Montecucco C (2000) Neurotoxins affecting neuroexocytosis. Physiol Rev 80 717-66... 

The clostridial neurotoxins are the most toxic substances known to science. The neurotoxin produced from Clostridium tetani (tetanus toxin) is encountered by humans as a result of wounds and remains a serious public health problem in developing countries around the world. However, nearly everyone reared in the western world is protected from tetanus toxin as a result of the ordinary course of childhood immunizations. Humans are usually exposed to the neurotoxins produced by Clostridium botulinum (ie, the botu-linum toxins, of which there are seven in all) by means of food poisoning, although there are rare incidents of wound botulism and a colonizing infection of neonates known as infant botulism.1 Since the incidence of botulinum poisoning by all routes is very rare,... 

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