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. ? ? ?
