Evaluation in Primates of Cocaine Esterase for the Treatment of Cocaine Toxicity

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DESCRIPTION (provided by applicant): Cocaine esterase (CocE) is a product of the bacterium Rhodococcus sp. which grows in the rhizospheres of coca plants in South America. The bacterium uses CocE to break down cocaine to provide its sole source of carbon and nitrogen. CocE is the most efficient cocaine esterase yet observed. We have studied it in vitro and in vivo in rodents and found that it is able to reverse immediately the effects of lethal doses of cocaine in these animals. Although CocE appears to be a superb treatment for cocaine overdose, its usefulness as a treatment for cocaine abuse is limited by its very short half life. A funded grant (DA021416) is currently developing mutants of CocE that have greater thermostability and longer durations of action and testing them in rodent models of cocaine toxicity. The purpose of the current application is to evaluate native CocE in non-human primates as a step in the process of making this enzyme available for treatment of cocaine overdose in humans. Each year of the project will evaluate a single version of CocE, starting with the native enzyme, and proceeding through mutants that have been shown to have substantially longer durations of action. Three types of studies will be conducted sequentially in each year with each enzyme. The first will identify effective doses of the enzyme for reducing the cardiovascular effects of cocaine and clearing a range of doses of cocaine from the plasma of rhesus monkeys. The second study will focus on measuring immunological responses to each enzyme when it is administered repeatedly at intervals that should maximize development of titers. The effect of CocE titer development on the ability of the enzyme to reduce the effects of cocaine will also be studied in this process. The third study involves determination of the ability of CocE and its longer-acting mutants to prevent the reinforcing effects of cocaine and to modify the cardiovascular effects of self-administered cocaine. Dose-response functions for each enzyme will be obtained repeatedly and blood samples analyzed for titer development so that tolerance to the effects of CocE can be monitored.