Botulinum Journal

The drug discovery 'pipeline' guides the evolution of therapeutic products from initial discovery to clinical trials. Given limited resources, optimisation of this process is critical and can be addressed through the creation of product development tools. Strong drug candidates for botulism have yet to be identified, but with continued and focused efforts it is likely a lead candidate will emerge. Formal description of the desired therapeutic product, and a mechanism to evaluate potential drug products, must be established to facilitate selection of promising inhibitor compounds. This approach will conserve resources and increase the probability of developing a successful therapeutic product. [Received 25 October 2007; Accepted 4 November 2007]

Andrea M. Stahl

Michael Adler

Charles B. Millard

Lynne Gilfillan

The Botulinum J

Product development tools to enhance drug discovery

增强药物发现的产品开发工具

Botulinum Neurotoxin (BoNT) is responsible for botulism, a severe and often deadly disease. Light chain of BoNT behaves as endopeptidase, cleaving the SNARE proteins, and inhibits the neurotransmitter release. A double-mutant E224A/E262A full-length BoNT Type A was successfully cloned and expressed in E. coli. The purified protein lacks the endopeptidase activity involved in the toxic action, and is structurally compatible with the native BoNT/A. Thus this molecule not only can be used as a safe surrogate for study of BoNT, but also can be potentially used as an antidote against botulism, and as a vaccine candidate for botulism.

Weiping Yang

Paul Lindo

Stephen Riding

Tzuu Wang Chang

Shuowei Cai

Thuan Van

Roshan Kukreja

Yu Zhou

Kruti Vasa

Bal Ram Singh

Expression, purification and comparative characterisation of enzymatically deactivated recombinant botulinum neurotoxin type A

酶解失活重组肉毒杆菌神经毒素A型的表达、纯化及比较表征

A Computer-Assisted Communication Device (CACD) was developed for patients paralysed by botulinum neurotoxin (BoNT) who are unable to speak due to toxin-induced dysphonia or obstruction from an endotracheal tube for assisted ventilation. The system uses pre-programmed menus and synthetic speech to allow for patient-initiated communication. The CACD was designed to meet the needs of patients who possess normal cognition and hearing, but impaired vision, and who are extensively paralysed but still able to press a switch to make menu choices. The CACD will allow patients to interact more effectively with their health care providers which should aid in their recovery.

Richard E. Sweeney

Computer-Assisted Communication Device for botulinum-intoxicated patients

肉毒中毒患者计算机辅助沟通装置

Lama immunoglobulins consist of conventional antibody (IgG1) and unique forms that lack light chains, called heavy chain antibodies (IgG2 and IgG3). These unusual antibodies possess unique properties ideal for diagnostics and therapeutics. To evaluate the IgG from a llama immunised with botulinum complex toxoids A through F each IgG subclass was tested as capture and recognition ligand in xMAP fluid array immunoassays. The optimal combination, IgG3 capture and IgG2 tracer, detected as low as 64 pg/ml of BoNT/A complex toxoid. Also, heavy chain antibodies were shown to bind BoNT as effectively as conventional IgG1, while possessing much greater thermal stability. [Received 15 October; Accepted 28 December 2007]

George P. Anderson

Yakelin A. Ortiz Vera

Andrew Hayhurst

Jill Czarnecki

Jason Dabbs

BaoHan Vo

Ellen R. Goldman

Evaluation of llama anti-botulinum toxin Heavy chain Antibody

评估羊驼抗肉毒杆菌毒素重链抗体

Over the past decade, a plethora of new detection methods for Clostridium botulinum Toxins (BoNTs) have been introduced into the bioresearch and bio-defense communities. These methods are on the promise that the detection of BoNTs would be comparable with the mouse bioassay. Furthermore, these methods would be leveraged as a high-throughput system that would identify contaminants more quickly for counter-terrorism purposes. But, few truly novel detection methods have made significant progress. For new advances, challenges, limitations and strategies in the detection, a comprehensive validation strategy is a means to garner equal attention for the successful development of a detection method.

Shashi K. Sharma

Here a method, there a method, everywhere many methods. What should a laboratory do to validate an assay for the detection of botulinum neurotoxins?

这里一种方法，那里一种方法，到处都是许多方法。实验室应该如何验证用于检测肉毒杆菌神经毒素的检测方法？

After the extraordinary success of botulinum toxin serotype A in the 1980s to treat a wide range of spasmodic muscular conditions and movement disorders, a significant number of patients were found to stop responding to their treatments with time. When investigated, they were found to have become immune ('resistant') to the products. This second article in a series looks at the next botulinum toxin serotype used clinically after serotype A to overcome this resistance and how that choice was made.

Andy Pickett

Historical aspects of botulinum toxin used clinically: part II: overcoming resistance

肉毒杆菌毒素临床应用的历史方面：第二部分：克服耐药性

Clostridium botulinum toxin is one of the potent and classic molecules known to this modern scientific research field. It has dualistic characters: on one hand it causes botulism by blocking release of acetylcholine at the cholinergic nerve endings and on the other hand the same toxin molecule when administered locally at sub-lethal dose relieves various neuromuscular disorders. If the toxin is used intentionally as an act of terrorism, FDA approved therapeutic agents would be needed to recover from the illness. In addition, to prevent from such situations in the future and to protect public from botulism, there is a strong need for a mucosal vaccine. Creating a multivalent mucosal vaccine delivery system would ease the burden at the time of delivery and reduce the cost.

Easwaran Ravichandran

Perspectives on mucosal vaccine against botulism

抗肉毒杆菌黏膜疫苗的展望

Botulinum neurotoxins (BoNTs) are potent toxins, which block the neurotransmitter release at neuromuscular junctions and are responsible for a severe disease, the botulism. In the natural disease, BoNTs are the most frequently acquired by the oral route. BoNT associates to non-toxic proteins (ANTPs), which have a main role in toxin protection against acidic pH and proteases, especially in the gastrointestinal tract. BoNTs which transit through the digestive tract, have first to cross the epithelial barrier. BoNTs are able to undergo a receptor-mediated transcytosis, which delivers the whole and active toxin at the basolateral side of epithelial cells. ANTPs containing hemagglutinins have an additional role in altering the intercellular junctions and facilitating a toxin passage through the paracellular way. Then, BoNT disseminates locally and at distance via the blood/lymph circulation and possibly via a retrograde axonal transport to the target motoneuron endings, where the toxin uses an endocytic pathway permitting the release of the light chain into the cytosol and its subsequent proteolytic activity towards the SNARE proteins involved in the neurotransmitter exocytosis.

Chloé Connan

Michel R. Popoff

Botulinum neurotoxins: from the gut to the nervous system

肉毒杆菌神经毒素：从肠道到神经系统

Botulinum neurotoxins (BoNTs) are the most toxic substances to mankind, and yet, there are no therapeutics available to reverse the paralysis, the deadly symptom of botulism caused by BoNTs. Here we report that RNA aptamer, selected through in vitro process against light chain of botulinum neurotoxin type A (BoNT/A) showed in vivo protection efficacy against botulism. Our results showed that RNA aptamer not only accelerated the recovery of local paralysis induced by BoNT/A through mouse exercise wheel assay, but also significantly delayed the time-to-death through mouse protection assay, and rescued one mouse (out of six) completely intoxicated by BoNT/A. Our results demonstrated the potential using RNA aptamer as antidote against deadly botulism.

Pavithra Janardhanan

RNA aptamer as potential antidote against botulism: an in vivo report

RNA适体作为抗肉毒中毒潜在解毒剂：体内报告

Botulism had mortality rates >60% before the 1950s. We reviewed confirmed botulism cases in the USA during 1975-2009 including infant, foodborne, wound, and other/unknown acquisition categories, and calculated mortality ratios. We created a multivariate logistic regression model for non-infant cases (foodborne, wound, and other/unknown). Overall mortality was 3.0% with 109 botulism-related deaths among 3,618 botulism cases [18 (<1%) deaths among 2,352 infant botulism cases, 61 (7.1%) deaths among 854 foodborne botulism cases, 18 (5.0%) deaths among 359 wound botulism cases, and 12 (22.6%) deaths among 53 other/unknown botulism cases]. Mortality among all cases increased with age; it was lowest among infants (0.8%) and highest among persons ≥80 years old (34.4%). Toxin type F had higher mortality (13.8%) than types A, B, or E (range, 1.4% to 4.1%). Efforts to reduce botulism mortality should target non-infant transmission categories and older adults.

Kelly A. Jackson

Barbara E. Mahon

John Copeland

Ryan P. Fagan

Botulism mortality in the USA, 1975-2009

美国1975-2009年肉毒中毒死亡率

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