Catalytic Bioscavengers with Broad Specificity Against OP Nerve Agents

对 OP 神经毒剂具有广泛特异性的催化生物清除剂

• 批准号: 7294970
• 负责人: James Robert Wild
• 金额: $ 36.69万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-29 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7294970
• 关键词: Acids; Address; Adverse effects; Animal Model; Animals; Antidotes; Blood Circulation; Cavia; Chemical Warfare; Chemical Warfare Agents; Chemicals; Consultations; Data; Data Analyses; Dendrimers; Development; Disadvantaged; Dose; Drug Kinetics; Encapsulated; Engineering; Enzymes; Event; Experimental Designs; Exposure to; Goals; Histopathology; Human; Human Resources; Hydrolase; Hydrolysis; In Vitro; Injection of therapeutic agent; Intervention; Intoxication; Intramuscular; Lead; Lethal Dose 50; Mammals; Medical; Military Personnel; Mission; Mus; Organism; Organophosphorus Compounds; Pathology; Pesticides; Poison; Poisoning; Population; Positioning Attribute; Preparation; Production; Proteins; Public Health; Research; Research Personnel; Route; Safety; Sarin; Soldier; Soman; Specificity; Sterically Stabilized Liposome; Structure; Students; Substrate Specificity; Survivors; Techniques; Technology; Testing; Therapeutic; Time; Toxic effect; Treatment Protocols; United States Food and Drug Administration; Veterinary Medicine; Week; Work; antinerve agent; aryldialkylphosphatase; base; bioscavenger; college; concept; cyclosarin; design; efficacy evaluation; experience; gallium alloy GF; improved; in vivo; member; nerve agent; neurotoxic; novel strategies; pharmacokinetic model; pre-clinical; programs; prophylactic; research study; residence; tabun

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.

描述（由申请人提供）：该项目的中心假设是，可以开发具有广泛底物特异性的催化生物清除剂，作为针对高优先级有机磷（OP）神经毒剂的安全有效的医疗对策。目前存在一组充分表征的酶，天然的和工程化的，其已被评估为针对OP神经毒剂的治疗剂或预防剂。初步研究表明，这些酶中的一些可以保护小鼠免受某些OP农药暴露高达800 x LD 50的毒性影响。目前开发这些酶作为有效的生物清除剂的主要障碍是它们从哺乳动物的循环中快速清除，导致体内停留时间短。初步研究表明，这些酶的封装有可能提供所需的延长的停留时间。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，其保护免受至少5 × LD 50的暴露;保护本身应该是安全的，持久的（> 3周持续时间）和广谱的。该项目的具体目标是生产、封装和提供所选催化生物清除剂的基本药代动力学有效性评价：具体目标1。生产和测试包封酶在体外水解OP神经毒剂的能力;具体目标2。生成并比较IM递送至豚鼠后所选生物清除剂的药代动力学特征;具体目标3.确定由催化生物清除剂与OP神经毒剂提供的保护比率。CounterAct U 01计划的既定使命是“开发新的和改进的针对化学威胁的医学对策”;此处提出的研究将通过提供针对OP神经毒剂的新的、有效的和安全的医学对策来解决这一使命。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OP农药。在这些研究中将被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和文职人员具有双重用途。