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.
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.
|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|
|Orson, Frank M; Wang, Rongfu; Brimijoin, Stephen et al. (2014) The future potential for cocaine vaccines. Expert Opin Biol Ther 14:1271-83|
|Gao, Jun; Li, Yonghui; Zhu, Ning et al. (2013) Roles of dopaminergic innervation of nucleus accumbens shell and dorsolateral caudate-putamen in cue-induced morphine seeking after prolonged abstinence and the underlying D1- and D2-like receptor mechanisms in rats. J Psychopharmacol 27:181-91|
|Larrimore, Katherine E; Barcus, Matthew; Kannan, Latha et al. (2013) Plants as a source of butyrylcholinesterase variants designed for enhanced cocaine hydrolase activity. Chem Biol Interact 203:217-20|
|Gao, Yang; Geng, Liyi; Orson, Frank et al. (2013) Effects of anti-cocaine vaccine and viral gene transfer of cocaine hydrolase in mice on cocaine toxicity including motor strength and liver damage. Chem Biol Interact 203:208-11|
|Brimijoin, Stephen; Shen, Xiaoyun; Orson, Frank et al. (2013) Prospects, promise and problems on the road to effective vaccines and related therapies for substance abuse. Expert Rev Vaccines 12:323-32|
|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|
|Brimijoin, Stephen; Gao, Yang (2012) Cocaine hydrolase gene therapy for cocaine abuse. Future Med Chem 4:151-62|
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