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

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1DA031340-03
Application #
8306233
Study Section
Special Emphasis Panel (ZDA1-SXC-E (16))
Program Officer
Patel, Amrat
Project Start
2010-09-30
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$764,845
Indirect Cost
$279,845
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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
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
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
Chen, Vicky Ping; Gao, Yang; Geng, Liyi et al. (2015) Radiometric assay of ghrelin hydrolase activity and 3H-ghrelin distribution into mouse tissues. Biochem Pharmacol 98:732-9
Chen, Xiabin; Huang, Xiaoqin; Geng, Liyi et al. (2015) Kinetic characterization of a cocaine hydrolase engineered from mouse butyrylcholinesterase. Biochem J 466:243-51
Chen, Vicky Ping; Gao, Yang; Geng, Liyi et al. (2015) Plasma butyrylcholinesterase regulates ghrelin to control aggression. Proc Natl Acad Sci U S A 112:2251-6
Mor, Tsafrir S (2015) Molecular pharming's foot in the FDA's door: Protalix's trailblazing story. Biotechnol Lett 37:2147-50
Murthy, Vishakantha; Geng, Liyi; Gao, Yang et al. (2015) Reward and Toxicity of Cocaine Metabolites Generated by Cocaine Hydrolase. Cell Mol Neurobiol 35:819-26
Orson, Frank M; Wang, Rongfu; Brimijoin, Stephen et al. (2014) The future potential for cocaine vaccines. Expert Opin Biol Ther 14:1271-83
Murthy, Vishakantha; Gao, Yang; Geng, Liyi et al. (2014) Preclinical studies on neurobehavioral and neuromuscular effects of cocaine hydrolase gene therapy in mice. J Mol Neurosci 53:409-16

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