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3 - Botulinum toxin: from menace to medicine

Published online by Cambridge University Press:  02 December 2009

Peter Hambleton
Affiliation:
Health Protection Agency, Porton Down, Salisbury, UK
Andrew M. Pickett
Affiliation:
Ipsen Limited, 190 Bath Road, Slough, UK
Clifford C. Shone
Affiliation:
Health Protection Agency, Porton Down, Salisbury, UK
Anthony B. Ward
Affiliation:
University Hospital of North Staffordshire
Michael P. Barnes
Affiliation:
Hunters Moor Regional Neurological Rehabilitation Centre
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Summary

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The neurotoxins produced by the bacterium Clostridium botulinum that cause botulism are the most potent acute toxins known. There is no known cure for the flaccid muscular paralysis of botulism and for many people the disease evokes an emotive and fearful view of the toxins. Although rare, botulism is usually encountered as a food-borne disease that results from eating food contaminated with pre-formed toxin. Wound botulism and infant botulism are two other forms of the disease, although unlike food-borne botulism, these intoxications result from direct infection with the bacterium. The incidence of wound botulism has increased in recent years in drug users who inject heroin; infant botulism is now the most common form of the disease reported in the USA. Whilst these various forms of acquired botulism are frightening enough prospects, the toxins are now seen in the even more sinister context of use in weapons of biological warfare or bio-terrorism.

The perception of these potent microbial toxins is changing. Whilst the pharmaceutical industry annually spends many millions of pounds searching for or designing synthetic chemicals that have specific pharmacological activities, with the botulinum neurotoxins, nature has done all the work for us. Over aeons of time a family of molecules have evolved having a unique combination of biological activities that can be used to clinical benefit.

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Publisher: Cambridge University Press
Print publication year: 2007

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References

Scott, A. B., Rosenbaum, A. L. and Collins, C. C. (1973). Pharmaceutical weakening of extraocular muscles. Invest. Ophthalmol., 12, 924–7.Google Scholar
Scott, A. B. (1979). Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmol., 87, 1044–9.CrossRefGoogle Scholar
Marsden, C. D. and Quinn, N. P. (1990). The dystonias. Neurological disorders affecting 20,000 people in Britain. Brit. Med. J., 300, 139–44.CrossRefGoogle Scholar
Jankovic, J. and Brin, M. F. (1991). Therapeutic uses of botulinum toxin. New Engl. J. Med., 324, 1186–94.Google ScholarPubMed
Jankovic, J. and Hallett, M. (eds.) (1994). Therapy with Botulinum Toxin. New York: Marcel Dekker Inc.Google ScholarPubMed
Eleopra, R., Tugnoli, V., Rossetto, O., Montecucco, C. and Grandis, D. (1997). Botulinum neurotoxin serotype C: a novel effective botulinum toxin therapy in humans. Neurosci. Lett., 224, 91.CrossRefGoogle Scholar
Eleopra, R., Tugnoli, V., Quatrale, R., Gastaldo, E., Rossetto, O., Grandis, D. and Motecucco, C. (2002). Clin. Neurophysiol., 113, 1258–64.CrossRef
Eleopra, R., Tugnoli, V., Rossetto, O., Grandis, D. and Motecucco, C. (1998). Different time courses of recovery after poisoning with botulinum neurotoxin serotypes A and E in humans. Neuroscience Lett., 256, 135–8.CrossRefGoogle Scholar
Chen, R., Karp, B. I. and Hallett, M. (1998). Botulinum toxin type F for treatment of dystonia: long term experience. Neurology, 51, 1494–6.CrossRefGoogle ScholarPubMed
Tugnoli, V., Marchese Ragona, R., Eleopra, R., Grandis, D. and Montecucco, C. (2001). Treatment of Frey Syndrome with botulinum toxin type F. Arch. Otolaryngol. Head Neck Surg., 127, 339–40.Google ScholarPubMed
Sheean, G. L. and Lees, A. J. (1995). Botulinum toxin F in the treatment of torticillis clinically resistant to botulinum toxin A. J. Neurol. Neurosurg. Psychiatry, 59, 601–7.CrossRefGoogle ScholarPubMed
Greene, P. E. and Fahn, S. (1996). Response to botulinum toxin F in seronegative botulinum toxin A-resistant patients. Movement Disorders, 14, 181–4.CrossRefGoogle Scholar
Melling, J., Hambleton, P. and Shone, C. C. (1988). Clostridium botulinum toxins: nature and preparation for clinical use. Eye, 2, 16–23.CrossRefGoogle ScholarPubMed
Botulinum toxin type for injection. European Pharmacopoeia 5.8 (2007), 01/2005: 2113.
Bigalke, H. and Frevert, J. (1999). PCT patent application (PCT/DE00/0177) Therapeutic agent comprising a botulinum neurotoxin.
Bigalke, H. and Frevert, J. (1998). German patent application (DE19856897) Therapy for the control of snoring noises.
Requirements for Botulinum Toxin A for Therapeutic Use (2000). Pharmacopoeia of the Peoples Republic of China, 314–18.
McLellan, K., Gaines Das, R. E., Ekong, T. A. N. and Sesardic, D. (1996). Therapeutic botulinum type A toxin: factors affecting potency. Toxicon, 34, 975–85.CrossRefGoogle Scholar
Hambleton, P. and Pickett, A. M. (1994). Dose equivalence of botulinum toxin preparations (Letter). J. R. Soc. Med., 87, 719.Google Scholar
Pearce, L. B., Borodic, G. E., First, E. R. and McCallum, B. D. (1994). Measurement of botulinum toxin activity: evaluation of the lethality assay. Toxic Appl. Pharmacol., 128, 69–79.CrossRefGoogle Scholar
Sesardic, D., McLellan, K., Ekong, T. A. N. and Gaines Das, R. E. (1996). Refinement and validation of an alternative bioassay for potency testing of therapeutic botulinum type A toxin. Pharmac. Toxic., 78, 283–8.CrossRefGoogle ScholarPubMed
Sawtell, J. A. and Ream, A. J. (1995). Observations on the effect of the diluent used for diluting challenge toxin the clostridium botulinum potency assay. Biologicals, 23, 249–51.CrossRefGoogle Scholar
Schantz, E. J. and Kautter, D. A. (1978). Microbiological methods: standardization assay for Clostridium botulinum toxins. J. Ass. Analyt. Chem., 61, 96–9.Google Scholar
Brin, M. F. and Blitzer, A. (1993). Botulinum toxin: dangerous terminology errors (Letter). J. R. Soc. Med., 86, 493–4.Google Scholar
Sesardic, D. (2002). Alternatives in testing of bacterial toxins and antitoxins. In Brown, F., Hendrikson, C., Sesardic, D. and Cussler, K., eds., Advancing science and elimination of the use of laboratory animals for development and control of vaccines and hormones. Dev. Biol. Stand., 111, 101–8.Google Scholar
Peng, K., Merlino, G., Addeo, J., Foster, S., Spanoyannis, A. and Aoki, K. R. (1998). Botox® is six-fold more potent than Dysport® in the Mouse Digit Abduction Scoring Assay Movement Disorder Society 50th International Congress of Parkinson's Disease and Movement Disorders P2.102.
Sesardic, D., Gaines Das, R. E. and Corbel, M. J. C. (1997). Botulinum toxin. J. R. Soc. Med., 87, 307.Google Scholar
Shone, C. C., Appleton, N., Wilton-Smith, P., Hambleton, P., Modi, N., Gatley, S. and Melling, J. (1986). In vitro assays for botulinum toxins and antitoxins. In Davidson, I. and Hennessen, W., eds., Reduction of animal usage in the development and control of biological products. Dev. Biol. Stand. Basel: Karger, 64, 141–5.Google Scholar
Ekong, T. A. N., McLellan, K. and Sesardic, D. (1995). Immunological detection of Clostridium botulinum toxin type A in therapeutic preparations. J. Immun. Methods, 180, 181–91.CrossRefGoogle ScholarPubMed
Sesardic, D. (2002). Alternatives in testing of bacterial toxins and antitoxins. In Brown, F., Hendrikson, C., Sesardic, D. and Cussler, K., eds., Advancing science and elimination of the use of laboratory animals for development and control of vaccines and hormones. Basel: Karger, 111, 101–8.
Hallis, B., James, B. A. F. and Shone, C. C. (1996). Development of novel assays for botulinum type A and B neurotoxins based on their endopeptidase activities. J. Clin. Microbiol., 34, 1934–8.Google Scholar
Schantz, E. J. and Johnson, E. A. (1992). Properties and use of botulinum toxin and other microbial neurotoxins in medicine. Microbiological Reviews, 56(1), 80–99.Google Scholar
The Management, Design and Operation of Microbiological Containment Laboratories HSE Books, 2001, ISBN 0717620344.
Li Zhang, , Wei-Jen Lin, , Shengwen Li, and Roger Aoki, K. (2003). Complete DNA sequences of the botulinum neurotoxin complex of Clostridium botulinum type A-Hall (Allergan) strain. Gene, 315, 21–32.CrossRefGoogle Scholar
Bradshaw, M., Dineen, S. S. and Johnson, E. A. (2001). Regulation of Botulinum Neurotoxin Expression reviewed in Annual Report of the University of Wisconsin Food Research Institute, 2001, 13–15.
Hunt, T. J. (2000). PCT patent application (PCT/US01/03641) Botulinum Toxin Pharmaceutical Compositions.
Gill, D. M. (1982). Bacterial toxins: a table of lethal amounts. Microbiological Reviews, 46(1), 86–94.Google Scholar
Prescribing information for BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex, July 2002.
Food and Drug Administration Medical Officer's review of BOTOX® submission for treatment of glabellar facial lines, November 9, 2001 and March 4, 2002, page 10 (as published by FDA).
Aoki, K. R. (1999). Preclinical update on Botox (botulinum toxin type A)-purified neurotoxin complex relative to other botulinum toxin preparations. European Journal of Neurology, 6(Suppl. 4), S3–S10.CrossRefGoogle Scholar
Aoki, K. R. and Wheeler, L. (2000). A comparison of the efficacy and safety of Botox® and Dysport® in mice. Movement Disorders, 15(Suppl. 3), 35.Google Scholar
Aoki, K. R. and Guyer, B. (2001). Botulinum toxin type A and other botulinum toxin serotypes: a comparative review of biochemical and pharmacological actions. European Journal of Neurology, 8(Suppl. 5), 21–9.CrossRefGoogle ScholarPubMed
Inoue, K., Fujinaga, Y., Watanabe, T., Ohyama, T., Takeshi, K., Moriishi, K., Nakajima, H., Inoue, K. and Oguma, K. (1996). Molecular composition of Clostridium botulinum type A progenitor toxins. Infect. Immun., 64, 1589–94.Google ScholarPubMed
Ohishi, I., Sugii, S. and Sakaguchi, G. (1977). Oral toxicities of Clostridium botulinum in reponse to molecular size. Infect. Immun., 16, 107–9.Google Scholar
Dodd, S. L., Rowell, B. A., Vrabas, I. S., Arrowsmith, R. J. and Weatherill, P. J. (1998). A comparison of the spread of three formulations of neurotoxin A as determined by effects on muscle function. Eur. J. Neurol., 5, 181–6.CrossRefGoogle Scholar
Schiavo, G., Matteoli, M. and Montecucco, C. (2000). Neurotoxins affecting neuroexocytosis. Physiol. Rev., 80, 717–66.CrossRefGoogle ScholarPubMed
Boyd, R. S., Duggan, M. J., Shone, C. C. and Foster, K. A. (1995). The effect of botulinum neurotoxins on the release of insulin from insulinoma cell lines HIT-15 and RINm5F. J. Biol. Chem. (Commun.), 270, 18216–18.CrossRefGoogle ScholarPubMed
Gaisano, H. Y., Sheu, L., Foskett, J. K. and Trimble, W. S. (1994). Tetanus toxin light chain cleaves a vesicle-associated membrane protein (VAMP) isoform-2 in rat pancreatic zymogen granules and inhibits secretion. J. Biol. Chem., 269, 17062–6.Google Scholar
Chen, F., Foran, P., Shone, C. C., Foster, K., Melling, J. and Dolly, O. (1997). Botulinum type B inhibits insulin-stimulated glucose uptake into adipocytes and cleaves cellubrevin unlike type A toxin which failed to proteolyze the SNAP-23 present. Biochemistry, 36, 5719–28.CrossRefGoogle ScholarPubMed
Chaddock, J. A., Purkiss, J. R., Duggan, M. J., Quinn, C. P., Shone, C. C. and Foster, K. A. (2000a). A conjugate composed of nerve growth factor and a non-toxic derivative of botulinum neurotoxin type A can inhibit neurotransmitter releasein vitro. Growth Factors, 18, 147–55.CrossRefGoogle Scholar
Chaddock, K., Purkiss, J., Friss, L., Broadbridge, J., Duggan, M., Shone, C., Quinn, C. and Foster, K. (2000b). Inhibition of neurotoxin release by a retargeted endopeptidase derivative of C. botulinum type A. Infect. Immun., 68, 2587–93.CrossRefGoogle Scholar
Welch, M. J., Purkiss, J. R. and Foster, K. A. (2000). Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon, 38, 245–58.CrossRefGoogle ScholarPubMed
Duggan, M. J., Quinn, C. P., Chaddock, J., Purkiss, J. R., Alexander, F., Doward, S., Fooks, S. J., Friis, L., Hall, Y., Kirby, E., Leeds, N., Moulsdale, H. J., Dickenson, A., Green, M., Rahman, W., Suzuki, R., Shone, C. C. and Foster, K. A. (2002). Inhibition of release of neurotransmitters from rat dorsal root ganglia by a novel conjugate of a Clostridium botulinum toxin A endopeptidase fragment and Erythrina cristagalli lectin. J. Biol. Chem., 277, 34846–52.CrossRefGoogle ScholarPubMed
Bigalke, H. and Frevant, J. (2003). US patent application (US2003059912): Hybrid protein for inhibiting the degranulation of mastocytes and the use thereof.
Francis, J. W., Brown, R. H., Figueiredo, D., Remington, M. P., Castillo, O., Schwarzschild, M. A., Fishman, P. S., Murphy, J. R. and vanderSpec, J. C. (2000). Enhancement of diphtheria toxin potency by replacement of the receptor binding domain with tetanus toxin C-fragment: a potent vector for delivering heterologous proteins to neurons. J. Neurochem., 74, 2528–36.CrossRefGoogle Scholar
Schneider, H., Groves, M., Muhle, C., Reynolds, P. N., Knight, A., Themis, M., Carvajal, J., Scaravilli, F., Curiel, D. T., Fairweather, N. F. and Coutelle, C. (2000). Retargeting of adenoviral vectors to neurons using the Hc fragment of tetanus toxin. Gene Ther., 18, 1584–92.CrossRefGoogle Scholar
Knight, A., Carvajal, J., Schneider, H., Coutelle, C., Chamberlain, S. and Fairweather, N. (1999). Non-viral neuronal gene delivery mediated by the Hc fragment of tetanus toxin. Eur. J. Biochem., 259, 762–9.CrossRefGoogle Scholar
Goodnough, M. C., Oyler, G., Fishman, P. S., Johnson, E. A., Neale, E. A., Keller, J. E., Tepp, W. H., Clark, M., Hartz, S. and Adler, M (2002). Development of a neuronal delivery vector for the intracellular transport of botulinum neurotoxin agonists. FEBS Lett., 513, 163–8.CrossRefGoogle Scholar
Li, Y., Foran, P., Lawrence, G., Mohammed, N., Chan-Kwo-Chion, C. K., Lis, G., Aoki, R. and Dolly, J. O. (2001). Recombinant forms of tetanus toxin engineered for examining and exploiting neuronal trafficking pathways. J. Biol. Chem., 276, 31394–401.CrossRefGoogle ScholarPubMed
Dolly, J. O., Wheeler, L. A., Aoki, R. K. and Garst, M. A. (2001). US Patent application (US62003794): Modification of clostridial toxins for use as transporter proteins.
Simpson, L. L., Maksymowych, A. B. and Kiyatkin, N. (1999). Botulinum toxin as a carrier for oral vaccines. Cell. Mol. Life Sci., 56, 47–61.CrossRefGoogle ScholarPubMed
Park, J. B. and Simpson, L. L. (2003). Inhalation poisoning by botulinum toxin and inhalation vaccine with its heavy chain component. Infect. Immun., 71, 1147–54.CrossRefGoogle ScholarPubMed

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