Enhanced bioscavenger for medical countermeasures against organophosphorus agents

DESCRIPTION (provided by applicant): Counteracting the threat of intoxication by organophosphorus nerve agents (OP's) is an important mission for homeland security as well as for treating workers exposed to pesticides. OP's act on acetylcholinesterase to prevent synaptic inactivation, thereby leading to immobilization and death on sustained application. Currently, the most promising strategy to counter OP intoxication is to scavenge the agents using recombinant butyrylcholinesterase (rBChE), the major cholinesterase in human which has low substrate specificity and thus offers broad spectrum protection by binding OP's prior to their damaging neurons. Natural BChE levels are too low to afford protection however, and exogenous enzymes are required. PEGylated rBChE offers improved bioavailability and protection relative to recombinant enzymes, however the lifetime is still insufficiently long for effective prophylaxis and the bioavailability is still low, requiring larger doses for an effective therapy. Luna propose an alternative strategy to enhance and extend the efficacy of recombinant BChE in vivo based on a novel, proven protein formulation technology. Recombinant BChE is encapsulated in polysaccharide microgel preparations to provide sustained release of enzymes with much enhanced bioavailability and pharmacokinetics. Success of the program will provide a valuable medical countermeasure tool for enhanced OP prophylaxis or sustained treatment of OP intoxication. The final product could be an important addition to the Strategic National Stockpile. This proposed technology enhances the nation's preparedness against OP warfare agents and thus is of great interest to the public health. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Project Narrative Counteracting the threat of intoxication by organophosphorus nerve agents (OP) is an important mission for homeland security as well as for treating workers exposed to pesticides. Currently, the most promising strategy to counter OP intoxication is toscavenge the agents using recombinant butyrylcholinesterase; however its pharmacokinetics and bioavailability limit the practical applications for effective prophylaxis or sustained treatment o OP intoxication. This project proposes the development of sustained release bioscavenger formulations as enhanced medical countermeasures against OP warfare agents.