Catalytic Bioscavengers with Broad Specificity Against OP Nerve Agents

描述（由申请人提供）：本项目的中心假设是，具有广泛底物特异性的催化生物清除剂可以开发为安全有效的医疗对策，以对抗高优先级有机磷（OP）神经毒剂。目前存在一组特性良好的酶，既有天然的，也有工程的，它们已被评估为治疗或预防OP神经毒剂的药物。初步研究表明，其中一些酶可以保护小鼠免受接触某些有机磷农药高达800倍LD50的毒性影响。目前发展这些酶作为有效的生物清除剂的主要障碍是它们被认为从哺乳动物的循环中迅速清除，导致体内停留时间短。初步研究表明，这些酶的包封有可能提供所需的延长停留时间。这项研究的长期目标是生产OP神经毒剂的催化生物清除剂，防止至少5倍的LD50暴露；保护本身应该是安全的，持久的（大约3周的持续时间），广谱的。该项目的具体目标是生产、封装并为选定的催化生物清除剂提供必要的药代动力学疗效评估。制备并测试包封酶体外水解OP神经毒剂的能力；具体目标2。生成并比较所选生物清除剂在给药豚鼠后的药代动力学特征；具体目标3。确定催化生物清除剂与OP神经毒剂提供的保护比率。“对抗U01”计划的既定任务是“开发新的和改进的医疗对策，以应对化学威胁”；这里提出的研究将通过提供针对OP神经毒性毒剂的新的、有效和安全的医学对策来解决这一任务。该研究旨在提供适合提交给FDA的临床前药代动力学和疗效数据，以支持IND申请。与公共卫生的相关性在于认识到民用化学品威胁范围现在包括神经毒剂和其他化学品，包括有机磷农药。在这些研究中将描述的催化生物清除剂将在涉及神经毒剂或有机磷农药的大规模伤亡情况下，对军事和文职人员具有双重用途。

DESCRIPTION (provided by applicant): The central hypothesis of this project is that catalytic bioscavengers with broad substrate specificity can be developed as safe and effective medical countermeasures against the high priority organophosphorus (OP) nerve agents. There currently exist a panel of well-characterized enzymes, both native and engineered, which have been evaluated as therapeutic or prophylactic agents against OP nerve agents. Preliminary studies have demonstrated that some of these enzymes can protect mice against the toxic effects of exposures up to 800 x LD50 for some OP pesticides. The current major obstacle to the development of these enzymes as effective bioscavengers is their presumed rapid clearance from the circulation of mammals resulting in short in vivo residence times. Preliminary studies indicate that encapsulation of these enzymes has the potential to provide the required extended residence times. The long term objective of this research is to produce catalytic bioscavengers of OP nerve agents that protect against a minimum of 5 x LD50 exposure; the protection should itself be safe, long lasting (> 3 weeks duration), and broad spectrum. The specific aims for this project are to produce, encapsulate and provide the essential pharmacokinetic efficacy evaluation for the selected catalytic bioscavengers: Specific Aim 1. Produce and test encapsulated enzymes for their capacity to hydrolyze OP nerve agents in vitro; Specific Aim 2. Generate and compare the pharmacokinetic profiles of the selected bioscavengers following IM delivery to guinea pigs; Specific Aim 3. Determine protective ratios provided by the catalytic bioscavengers with OP nerve agents. The stated mission of the CounterAct U01 program is "to develop new and improved medical countermeasures against chemical threats"; the studies proposed here will address this mission by providing new, effective and safe medical countermeasures against OP neurotoxic agents. The research is designed to provide pre-clinical pharmacokinetic and efficacy data suitable for submission to the FDA in support of an IND application. The relevance to public health lies in the recognition that the civilian chemical threat spectrum now includes nerve agents and other chemicals, including OP pesticides. The catalytic bioscavengers that will be characterized in these studies will have dual-use application for both military and civilian personnel in mass casualty scenarios involving either nerve agents or OP pesticides.