Hindawi Publishing CorporationJournal of ToxicologyVolume 2012, Article ID 678963, 2 pagesdoi:10.1155/2012/678963
Editorial
Medical Applications of Clostridia and Clostridial Toxins
Martha L. Hale,1 Shuowei Cai,2 and S. Ashraf Ahmed1
1 Integrated Toxicology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA2 Biochemistry Department, University of Massachusetts Dartmouth, 285 Old Westport Road,North Dartmouth, MA 02747-2300, USA
Correspondence should be addressed to Martha L. Hale, [email protected]
Received 4 September 2012; Accepted 4 September 2012
The bacterial genus Clostridium produces a diverse array ofprotein toxins, many of which have played an important rolein disease and medicine. Although initially known for theirability to do harm, many clostridial toxins have been shownto have therapeutic value for a diverse array of diseases. Thearticles included in this special issue provide insight intosome of that diversity and show that bacterial toxins remaina valuable storehouse for development of new therapeuticmeasures.
Perhaps the most known toxin therapeutics derived fromthe clostridial species are neurotoxins secreted by Clostridiumbotulinum. Treatment using BTX is remarkable in that theamount of toxin required is small and the beneficial effectsare dramatic, particularly considering the fact that manyof the conditions, such as dystonias and muscle spasms,do not respond to other pharmacological treatments. Overthe last few decades, BTX has also become cosmeticallyimportant and has created significant markets for the drug.Most commercial BTX products are not the pure toxin, buta combination of the toxin and toxin-associated proteins.While these progenitor toxins are safe, a purified form ofthe toxin would eliminate extraneous proteins and offer asafer drug. Clinical investigations conducted by Y. Matsukaand coworkers (J. Toxicol., 12, 2012) show that BTX purifiedover a lactose column was an effective treatment for urinaryincontinence and prostatic hyperplasia. Their studies providefurther data confirming that purified BTX can be used inlieu of progenitor toxins for treatment of many spasmodicconditions.
Although the focus of most BTX treatment has centeredupon using the toxin as a local paralytic to relieve spasm-related illness, new studies show also that BTX aids in the
treatment of other difficult-to-treat conditions. D. Intiso (J.Toxicol., 12, 2012) provides an excellent review showingthe positive effects of BTX as a supplement in treatmentstrategies in which the patient requires neurorehabilitativeintervention. In treating conditions such as cerebral palsy,stroke, sialorrhea, and other neuromuscular diseases, BTXpermits the individual to benefit from physical therapywhich is often extremely difficult without some musclerelaxation. New uses of BTX are not limited to rehabilitativeintervention, but as suggested by F. j. Lebeda and colleagues(J. Toxicol., 12, 2012), BTX treatment may enhance theprocesses of wound healing. By performing a systematicsearch of the literature, the authors developed a qualitativemodel that shows the possibility of using BTX therapy inwound healing. BTX therapy disrupts muscle spasms. Musclerelaxation around the wound would help to reduce pain andinflammation so that the healing process can proceed morequickly. This work and future studies show that many futuretreatments for a diverse array of diseases and conditions maybenefit from the therapeutic use of BTX.
While BTX may be the best known, other clostridialtoxin-based therapeutics are either currently available or indevelopmental phases, and three examples are included inthis issue. G. Krautz-Peterson et al. and B. Gao and A.McClane utilize clostridial toxin cell binding componentsas delivery vehicles for therapeutic agents. As with manyclostridia toxins, C. difficile toxins have a cell bindingcomponent and an enzymatic toxic component. These toxinsare somewhat unique in that they also contain a proteasewithin the toxin. G. Krautz-Peterson and colleagues showstudies that support the ability to link the cell bindingregion of C. difficile toxin B (TcdB) with a therapeutic agent.
2 Journal of Toxicology
When the agent is endocytosed, the protease cleaves thedrug from the TcdB and is free to act. Additionally, the cellreceptor region of TcdB may be replaced with another cellbinding receptor, such as the BTX cell receptor region (Hc),thus limiting the cell types to which the TcdB may bind.By combining a BTX inhibitor to the TcdB-Hc, the authorsindicate that this drug would provide a BTX inhibitor that isneeded to treat botulism.
Another avenue for utilizing clostridia toxins as thera-peutics has been advanced by the investigations of B. Gaoand A. McClane (J. Toxicol., 12, 2012) in their developmentof a therapeutic using C. perfringens enterotoxin (CPE). CPEbinds to claudin receptors found in tight junctions andcells expressing large amounts of the claudin receptor areparticularly susceptible to the cytolytic CPE. Because cancercells usually express large quantities of claudin on their cellsurface, the cells are fairly sensitive to CPE intoxication andCPE provides a natural cytolytic agent for many cancer cells.The primary problem associated with CPE therapy is thefact that the toxin is a protein and, as such, may induceantibodies against CPE which could reduce its effectivenessin vivo. B. Gao and A. McClane solve this problem byusing the primary receptor domain (C-CPE) to enhancepermeability and delivery of chemotherapeutic agents. Thetruncated size of C-CPE reduces immunogenicity problemswhile providing a claudin-binding component forthe agent.
The abundance of clostridial toxins with their specificsubstrates provides a wealth of new pharmacological agents.Combined with the ability to engineer clostridia or its toxinsto target specific cells and tissues, the possibilities seemendless. However, the utility of clostridia in medicine doesnot end with the clostridial proteins. As reviewed by B.Umer et al., the spores of many clostridia species have beendeveloped as cancer therapies. Solid tumors pose a problemto current therapies because the therapeutic cannot be evenlydistributed throughout the tumor, partly due to hypoxia andnecrotic areas of the tumor. Clostridia spores are strictlyanaerobic and will only colonize areas devoid of oxygen andtherefore seek out the tumor environment. The spores havebeen modified to improve their tumor cytolytic capabilities.This review gives an excellent overview of the field and showthe possibilities for using clostridia spores in therapy.
As shown by the diverse subjects presented in this specialissue, the same characteristics that make Clostridia excellentpathogens have also made the Clostridia an abundant sourcefor development of pharmacological agents. I would liketo thank those that contributed to this special issue. Theirinvestigations have given us more insight into the manymedical applications of Clostridia and its toxins. Theirwork provides the foundation for many new and innovativeways in which Clostridia may be harnessed to developmore effective treatments for many diseases and medicalconditions.
Acknowledgments
The views expressed in this article are those of the author anddo not necessarily reflect the official policy or position of the
Department of the Army, the Department of Defense, or theUS Government.
Martha L. HaleShuowei Cai
S. Ashraf Ahmed
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