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.
|Chen, Vicky Ping; Gao, Yang; Geng, Liyi et al. (2017) Butyrylcholinesterase gene transfer in obese mice prevents postdieting body weight rebound by suppressing ghrelin signaling. Proc Natl Acad Sci U S A 114:10960-10965|
|Gao, Yang; Geng, Liyi; Chen, Vicky Ping et al. (2017) Therapeutic Delivery of Butyrylcholinesterase by Brain-Wide Viral Gene Transfer to Mice. Molecules 22:|
|Chen, V P; Gao, Y; Geng, L et al. (2017) Butyrylcholinesterase regulates central ghrelin signaling and has an impact on food intake and glucose homeostasis. Int J Obes (Lond) 41:1413-1419|
|Larrimore, Katherine E; Kazan, I Can; Kannan, Latha et al. (2017) Plant-expressed cocaine hydrolase variants of butyrylcholinesterase exhibit altered allosteric effects of cholinesterase activity and increased inhibitor sensitivity. Sci Rep 7:10419|
|Chen, Vicky Ping; Gao, Yang; Geng, Liyi et al. (2016) Butyrylcholinesterase Deficiency Promotes Adipose Tissue Growth and Hepatic Lipid Accumulation in Male Mice on High-Fat Diet. Endocrinology 157:3086-95|
|Brimijoin, Stephen; Chen, Vicky Ping; Pang, Yuan-Ping et al. (2016) Physiological roles for butyrylcholinesterase: A BChE-ghrelin axis. Chem Biol Interact 259:271-275|
|Murthy, Vishakantha; Reyes, Santiago; Geng, Liyi et al. (2016) Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice. J Pharmacol Exp Ther 356:720-5|
|Hashikawa, Naoya; Ogawa, Takumi; Sakamoto, Yusuke et al. (2015) Time Course of Behavioral Alteration and mRNA Levels of Neurotrophic Factor Following Stress Exposure in Mouse. Cell Mol Neurobiol 35:807-17|
|Chen, Xiabin; Huang, Xiaoqin; Geng, Liyi et al. (2015) Kinetic characterization of a cocaine hydrolase engineered from mouse butyrylcholinesterase. Biochem J 466:243-51|
|Mor, Tsafrir S (2015) Molecular pharming's foot in the FDA's door: Protalix's trailblazing story. Biotechnol Lett 37:2147-50|
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