The goals of this project are to move forward as rapidly as possible in developing an effective and safe new biological treatment for cocaine abuse and bring this treatment to the point at which clinical trials are appropriate. The approach that will be taken utilizes gene transfer vectors to deliver a mutated version of human plasma butyrylcholinesterase (BChE), which efficiently hydrolyzes cocaine into metabolites that are largely devoid of toxicity and reward potential. A body of evidence from animal studies indicates that such an approach is capable of preventing and reversing cocaine toxicity while also reducing reward stimulus from the self-administered drug and antagonizing drug-primed reinstatement of drug-seeking behavior. The proposed work will be extended to include nonhuman primates and will widen the range and detail of observations relating to the safety of the cocaine hydrolase enzyme when delivered directly as injected protein and when delivered by gene transfer vectors. The nature and magnitude of therapeutic effects will also be examined in more detail than previously, using a range of pharmacokinetic and behavioral models. After further refinement of enzyme coding sequences for vector driven transduction in vivo, attention will also be given to the issue of producing the optimally effective vector in adequate quantities and under rigorously controlled conditions for ultimate use in humans.

Public Health Relevance

The practical outcome of the proposed work should be a convincing demonstration that gene therapy with a cocaine-destroying enzyme is a realistic prospect for treating cocaine users who are trying to become drug free and remain that way. If the project is successful, it will have shown that such a treatment is safe and effective in experimental animals and it will generate reagents that meet standards for use in humans. ADMINISTRATIVE NOTE ON SCORING: All NIDA Translational Avant Garde Award (DP1) applicants are e

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZDA1-SXC-E (16))
Program Officer
Shih, Ming L
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Mayo Clinic, Rochester
United States
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Murthy, Vishakantha; Gao, Yang; Geng, Liyi et al. (2014) Physiologic and metabolic safety of butyrylcholinesterase gene therapy in mice. Vaccine 32:4155-62
Zlebnik, Natalie E; Brimijoin, Stephen; Gao, Yang et al. (2014) Long-term reduction of cocaine self-administration in rats treated with adenoviral vector-delivered cocaine hydrolase: evidence for enzymatic activity. Neuropsychopharmacology 39:1538-46
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Brimijoin, Stephen; Orson, Frank; Kosten, Thomas R et al. (2013) Anti-cocaine antibody and butyrylcholinesterase-derived cocaine hydrolase exert cooperative effects on cocaine pharmacokinetics and cocaine-induced locomotor activity in mice. Chem Biol Interact 203:212-6
Geng, Liyi; Gao, Yang; Chen, Xiabin et al. (2013) Gene transfer of mutant mouse cholinesterase provides high lifetime expression and reduced cocaine responses with no evident toxicity. PLoS One 8:e67446
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