Organophosphorus (OP) pesticide poisoning is a leading cause of premature death in many developing countries, killing an estimated 200,000 people every year in the Asia-Pacific region alone. In North America and Europe, the situation is quite different. While pesticide poisoning does occur, the main risk of OP poisoning is from terrorist attacks on civilian populations - through the release of OP nerve gases in crowded spaces or perhaps introduction of highly toxic pesticides into water supplies. The acute toxicity of OPs is primarily due to inhibition of acetylcholinesterase (AChE). Current therapy for OP poisoning requires resuscitation and use of atropine, followed by administration of oximes to reactivate AChE. However, these antidotes have limited effectiveness and between 10 and 40% of patients, depending on the responsible OP, still die even with intensive care support. Although OP pesticides have been a clinical problem for 50 years, no new therapies have been introduced since the 1960s. Because early therapeutic interventions lead to improved outcomes after OP poisoning, a treatment that is safe and highly effective, and that can be given by first responders at the site of poisoning, should markedly improve outcome. Both bacteria and humans make enzymes that hydrolyze OP compounds. Recombinant bacterial OP hydrolases have the potential to provide an affordable, widely available, and safe treatment that is rapidly effective against a wide variety of OPs. CSIRO, Entomology, in Australia has developed a bacterial enzyme, called OpdA, with excellent in vitro catalytic activity against many currently used OPs. In proof-of-concept studies, we have shown that OpdA has excellent efficacy when used alone or with 2- PAM in rat models of parathion and dichlorvos poisoning. However, a number of further steps, including the proposed non-human primate studies, are required before clinical trials in humans with OP poisoning. The purposes of this grant are to develop a new non-human primate (NHP) model of parathion poisoning and to test the safety and efficacy of OpdA in this NHP model. Proof that the enzyme is safe and effective against parathion should provide the necessary impetus for further development for human use. Our central hypothesis is that OpdA is safe and improves survival after poisoning with parathion. If successful, the proposed research promises to improve public health by mitigating the acute toxic effects of pesticides after accidental, intentional, or suicidal poisoning. The research also has implications for the treatment of military personnel and civilians after nerve gas poisoning. ? ? ? ?
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