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Development of a Human Hydrolase to Treat Cocaine Abuse and Overdose: Rat Models

开发治疗可卡因滥用和过量的人类水解酶：大鼠模型

基本信息

批准号：
8132604
负责人：
WILLIAM Stephen BRIMIJOIN
金额：
$ 31.15万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8132604
关键词：
Abate Abstinence Address Adenovirus Vector Adverse effects Amphetamines Attenuated Automobile Driving Behavior Biology Brain Butyrylcholinesterase Cardiovascular system Cholinesterases Cocaine Cocaine Abuse Cocaine Dependence Cues Development Diffusion Dopamine Dopamine Antagonists Dose Drug Kinetics Drug or chemical Tissue Distribution Engineering Enzymes Evaluation Extinction (Psychology)Female Food Gene Transfer Generations Goals Half-Life Heart Hour Human Hydrolase Hydrolase Gene Immediate-Early Genes Injection of therapeutic agent Intervention Life Liver Maintenance Measures Metabolism Methods Modeling Molecular Motivation Motor Seizures Mus Mutagenesis Mutation Neostriatum Overdose Patients Pharmaceutical Preparations Phase Plasma Protein Engineering Proteins Rattus Recovery Relapse Research Rewards Rodent Route Safety Schedule Seizures Self Administration Self-Administered Signal Transduction Specificity Speed Staging Stem cells Structure Testing Therapeutic Therapeutic Agents Time Toxic effect Viral Vector Work addiction analog base behavior test cocaine esterase cocaine overdose design driving behavior drug maintenance drug of abuse drug seeking behavior gene induction gene therapy gene transfer vector helper-dependent adenoviral vector male metabolic abnormality assessment non-drug novel prevent programs response reward circuitry sex success

项目摘要

DESCRIPTION (provided by applicant): A novel concept for treatment of cocaine abuse envisages radically accelerated metabolism of cocaine as a means of reducing drug-seeking behavior. We propose a study of "metabolic therapy" for cocaine overdose and two critical stages of cocaine addiction: steady-state maintenance of drug self-administration, and drug-primed relapse or reinstatement of drug-seeking behavior after a period of abstinence. Our therapeutic agent is a human plasma cholinesterase converted by structure-driven mutagenesis into a cocaine hydrolase (CocH) that metabolizes cocaine with exceptional speed and is far more stable than bacterial cocaine esterase. Injections of this protein hastened drug elimination 100-fold or more, prevented toxicity from a lethal dose of cocaine given up to 12 hr later, and rescued rats from overdose even after convulsive seizures commenced. In preliminary trials this hydrolase prevented reinstatement of cocaine-seeking behavior in rats that had previously self-administered the drug. These findings indicate that long-term delivery of CocH might aid in dealing with cocaine abuse and its associated toxicity. The research plan addresses this prospect with three aims. FIRST are studies to extend the surprising finding that toxicity from cocaine overdose abates in seconds after CocH injection. Extensive pharmacokinetics and mechanistic studies of dopamine transients in the neostriatum of cocaine-challenged rats will test the hypothesis that recovery from seizures reflects the creation of steep cocaine diffusion gradients between brain and plasma. SECOND are tests of CocH on the motivation for cocaine self-administration in rats working under a progressive ratio schedule for several doses of drug. Rats will also be pretreated with CocH to further investigate its ability to block cocaine-primed reinstatement of cocaine-seeking behavior. THIRD are studies on CocH gene transfer. Preliminary results with a first-generation adenoviral gene transfer vector showed that high-level transduction of cocaine hydrolase in liver blocked the induction of delta-FosB in neostriatum, a molecular signal of cocaine addiction. We now plan to test advanced helper-dependent adenoviral vectors that should sustain expression for months in the periphery and the brain. Along with viral vectors we will also examine the delivery of hydrolase by modified stem cells. Our Research Plan is based on the premise that one or more of these gene-transfer approaches will suppress drug-seeking behavior in addicted rats and also reduce the propensity for relapse. This hypothesis, if substantiated, might later be extended to human patients. Previous attempts to block such behavior, which involves activation of dopaminergic reward circuitry, have used dopamine receptor antagonists. In contrast to the many side effects of those agents, we expect our proposed treatment to lack adverse effects at doses that suppress drug seeking. Our results should increase understanding of the biology of abuse and test the concept that cocaine abuse might be effectively treated by methods that prevent drug access to targets in the brain. Program Narrative: Recent advances in protein engineering have led to a human enzyme that destroys cocaine rapidly enough to prevent it from reaching the heart or brain. Our preliminary results show that this enzyme rescues rats from lethal seizures after drug overdose and also prevent formerly addicted rats from relapsing when they get access to cocaine. This application will investigate whether direct treatment or gene therapy with this enzyme can reduce drug-seeking behavior in rats as a model for cocaine addiction in humans.

描述(由申请人提供)：一种治疗可卡因滥用的新概念设想从根本上加速可卡因的新陈代谢，以此作为减少寻求毒品行为的一种手段。我们建议对可卡因过量的“代谢疗法”和可卡因成瘾的两个关键阶段进行研究：维持药物自我给药的稳定状态，以及戒断一段时间后药物诱导的复发或恢复寻药行为。我们的治疗剂是一种人血浆胆碱酯酶，通过结构驱动的突变转化为可卡因水解酶(COCH)，它以极快的速度代谢可卡因，比细菌可卡因酯酶稳定得多。注射这种蛋白质可以加速100倍或更多的药物消除，防止12小时后给予致命剂量的可卡因的毒性，并在惊厥发作开始后将大鼠从过量服用中解救出来。在初步试验中，这种水解酶阻止了先前自我给药的大鼠恢复寻找可卡因的行为。这些发现表明，长期服用可卡因可能有助于应对可卡因滥用及其相关毒性。该研究计划针对这一前景提出了三个目标。首先是扩展这一令人惊讶的发现的研究，即可卡因过量的毒性在注射可卡因后几秒钟内就会减弱。对可卡因攻击大鼠新纹状体中多巴胺瞬变的广泛药代动力学和机制研究将检验这一假说，即癫痫发作的恢复反映了脑部和血浆之间产生陡峭的可卡因扩散梯度。其次是可卡因对大鼠的可卡因自我给药动机的测试，这些大鼠是在按递增比率时间表工作的几种剂量的药物。还将用可卡因对大鼠进行预处理，以进一步研究其阻止可卡因诱导的可卡因寻找行为恢复的能力。三是Coch基因转移的研究。第一代腺病毒基因转移载体的初步结果表明，肝脏中高水平的可卡因水解酶转导阻断了新纹状体中Delta-FosB的诱导，新纹状体是可卡因成瘾的分子信号。我们现在计划测试先进的助手依赖型腺病毒载体，这些载体应该可以在外周和大脑中持续表达几个月。除了病毒载体，我们还将研究改良干细胞运送水解酶的情况。我们的研究计划是基于这样一个前提，即这些基因转移方法中的一种或多种将抑制成瘾大鼠的寻药行为，并降低复发的倾向。如果这一假设得到证实，以后可能会扩展到人类患者身上。以前试图阻止这种涉及激活多巴胺能奖赏电路的行为时，曾使用过多巴胺受体拮抗剂。与这些药物的许多副作用相比，我们预计我们提议的治疗方法在抑制药物寻找的剂量下将没有不良反应。我们的结果应该会增加对滥用生物学的理解，并测试这样一个概念，即通过防止药物进入大脑中的靶点的方法可以有效地治疗可卡因滥用。节目简介：蛋白质工程的最新进展导致了一种人类酶，它可以足够快地摧毁可卡因，防止它到达心脏或大脑。我们的初步结果表明，这种酶可以将大鼠从药物过量后的致命性癫痫发作中解救出来，并还可以防止以前上瘾的大鼠在获得可卡因后复发。这项应用将作为人类可卡因成瘾的模型，研究这种酶的直接治疗或基因治疗是否可以减少大鼠的寻药行为。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Preclinical studies on neurobehavioral and neuromuscular effects of cocaine hydrolase gene therapy in mice.

DOI：
10.1007/s12031-013-0130-5
发表时间：
2014-07
期刊：
Journal of molecular neuroscience : MN
影响因子：
0
作者：
Murthy V;Gao Y;Geng L;LeBrasseur N;White T;Brimijoin S
通讯作者：
Brimijoin S

Reward and Toxicity of Cocaine Metabolites Generated by Cocaine Hydrolase.

可卡因水解酶产生的可卡因代谢物的奖励和毒性。

DOI：
10.1007/s10571-015-0175-9
发表时间：
2015
期刊：
Cellular and molecular neurobiology
影响因子：
4
作者：
Murthy,Vishakantha;Geng,Liyi;Gao,Yang;Zhang,Bin;Miller,JordanD;Reyes,Santiago;Brimijoin,Stephen
通讯作者：
Brimijoin,Stephen

Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice.

可卡因水解酶基因转移证明了对小鼠心脏的安全性和对可卡因诱导的 QT 延长的功效。