Accelerating botulism therapeutic product development in the Department of Defense

Abstract

Coordinated small‐molecule drug discovery research efforts for the treatment of botulism by the public sector, especially the U.S. Department of Defense (DoD) and Department of Health and Human Services (DHHS), began in the 1990s and represent a significant resource investment. Organization of an effective botulism therapeutic drug program, however, presents formidable technical and logistical challenges. Seven distinct BoNT serotypes are known, each representing a different target. Moreover, BoNT exerts its action inside peripheral cholinergic neurons, and some serotypes may persist functionally within nerve cells for weeks or months. Clinical botulism occurs infrequently, and the effectiveness of prolonged mechanical ventilation to treat poisoning further limits experimental drug testing. The efficacy of experimental compounds must be extrapolated from disparate cell‐ or tissue‐based or rodent models. Numerous compounds with moderate efficacy in experimental laboratory assays have been reported, but may not possess the necessary safety, efficacy, and pharmacokinetic profile to support therapeutic development. To mitigate these challenges, we propose product development tools to assist in management of the BoNT portfolio and to clearly define the desired therapeutic product. Establishing a target product profile (TPP) is proposed to guide public sector managers toward critical aspects of the desired therapeutic product. Additional product development tools to assist in shaping research portfolios and to inform decisions regarding lead candidates to pursue are also discussed. Product development tools that facilitate the characterization of the ideal therapeutic product, and assist in the maintenance of a robust portfolio, will ameliorate the inherent financial risk in drug development for treating BoNT intoxication. Drug Dev Res 70:303–326, 2009. Published 2009 Wiley‐Liss, Inc.

Quantification of Botulinum Neurotoxin Serotypes A and B from Serum Using Mass Spectrometry

“…Activity quantification could identify when antitoxins and other medical countermeasures would be the most effective as one aspect of the botulism pharmacokinetic profile. 9 Serum based analysis also provides an advantage as stool collection may be problematic from botulism induced constipation. 5 The mouse bioassay (MBA) has historically been the most common method used to confirm clinical botulism and contains two distinct parts.…”

“…More importantly, the correlation between BoNT levels and clinical outcome is still largely unknown. Activity quantification could identify when antitoxins and other medical countermeasures would be the most effective as one aspect of the botulism pharmacokinetic profile . Serum based analysis also provides an advantage as stool collection may be problematic from botulism induced constipation …”

A High Content Imaging Assay for Identification of Botulinum Neurotoxin Inhibitors

“…The remaining serotypes cleave synaptobrevin (also called Vesicle-associated membrane protein (VAMP). BoNT/A was chosen for assay development as it is responsible for a high proportion of naturally occurring botulism and has the longest duration of action 6 . Development of small molecule therapeutics against BoNT/A is a major goal for our drug discovery program and has utilized traditional target-based methods to identify active site proteolytic inhibitors 7,[8][9][10] .…”