Catalytic Bioscavengers with Broad Specificity Against OP Nerve Agents

描述(申请人提供)：该项目的中心假设是，具有广泛底物特异性的催化生物清除剂可以被开发为针对高优先级有机磷(OP)神经毒剂的安全和有效的医学对策。目前有一组特性良好的酶，无论是天然的还是工程的，都已被评估为治疗或预防OP神经毒剂的药物。初步研究表明，这些酶中的一些可以保护小鼠免受某些OP杀虫剂高达800×LD50的暴露的毒性影响。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假定从哺乳动物的循环中迅速清除，导致较短的体内停留时间。初步研究表明，这些酶的包裹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，以防止至少5倍LD50暴露；保护本身应该是安全的、持久的(持续3周)和广谱的。本项目的具体目标是为所选的催化生物清除剂生产、包裹并提供必要的药代动力学效果评价：具体目标1.生产并测试包埋的酶在体外对OP神经毒剂的降解能力；具体目标2.产生并比较所选生物清除剂在IM给药后的药代动力学特征；具体目标3.测定催化生物清除剂与OP神经毒剂之间的保护率。“对抗U01”计划的既定使命是“开发针对化学威胁的新的和改进的医学对策”；这里提出的研究将通过提供针对OP神经毒剂的新的、有效和安全的医学对策来实现这一使命。这项研究的目的是提供临床前药代动力学和疗效数据，适合提交给FDA，以支持IND申请。与公众健康相关的是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OP杀虫剂。将在这些研究中描述的催化生物清除剂将在涉及神经毒剂或OP杀虫剂的大规模伤亡情况下对军事人员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.