Cocaine hydrolase gene therapy for cocaine abuse (DPI)

可卡因水解酶基因疗法治疗可卡因滥用 (DPI)

• 批准号: 8920215
• 负责人: WILLIAM Stephen BRIMIJOIN
• 金额: $ 11.87万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8920215
• 关键词: Address; Animals; Attention; BCHE gene; Behavior; Behavioral Model; Biological; Butyrylcholinesterase; Clinical Trials; Cocaine; Cocaine Abuse; Cocaine Users; Code; Enzymes; Gene Transfer; Genetic Transcription; Goals; Half-Life; Health; Human; Hydrolase; Hydrolase Gene; Light; Macaca mulatta; Modeling; Mutate; Mutation; Nature; Outcome; Pathology; Pharmaceutical Preparations; Plasma; Process; Production; Proteins; Quality Control; Reagent; Relapse; Research; Rewards; Rodent; Safety; Self-Administered; Smoke; Stimulus; System; Testing; Therapeutic Effect; Tissues; Toxic effect; Training; Translations; Validation; Work; cocaine exposure; drug seeking behavior; gene therapy; gene transfer vector; helper-dependent adenoviral vector; improved; in vivo; meetings; nonhuman primate; pharmacokinetic model; prevent; research study; response; therapeutic protein; vector

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：该项目的目标是尽快开发一种有效和安全的新的可卡因滥用生物治疗方法，并使这种治疗方法达到适合临床试验的程度。将采用的方法是利用基因转移载体传递一种突变的人血浆丁基胆碱酯酶（BChE），这种酶能有效地将可卡因水解成基本上没有毒性和回报潜力的代谢物。来自动物研究的大量证据表明，这种方法能够预防和逆转可卡因毒性，同时也能减少自我给药的奖励刺激，并对抗药物引发的寻求药物行为的恢复。拟议的工作将扩展到包括非人灵长类动物，并将扩大与可卡因水解酶直接作为注射蛋白质和通过基因转移载体传递时的安全性有关的观察范围和细节。使用一系列药代动力学和行为模型，也将比以前更详细地检查治疗效果的性质和程度。在进一步完善体内载体驱动转导的酶编码序列后，还将关注在严格控制的条件下，以足够的数量生产最有效的载体以最终用于人类的问题。

项目成果

Plants as a source of butyrylcholinesterase variants designed for enhanced cocaine hydrolase activity.

植物作为丁酰胆碱酯酶变体的来源，旨在增强可卡因水解酶活性。

• DOI: 10.1016/j.cbi.2012.09.004
• 发表时间: 2013
• 期刊: Chemico-biological interactions
• 影响因子: 5.1
• 作者: Larrimore,KatherineE;Barcus,Matthew;Kannan,Latha;Gao,Yang;Zhan,Chang-Guo;Brimijoin,Stephen;Mor,Tsafrir
• 通讯作者: Mor,Tsafrir

Plant-expressed cocaine hydrolase variants of butyrylcholinesterase exhibit altered allosteric effects of cholinesterase activity and increased inhibitor sensitivity.

• DOI: 10.1038/s41598-017-10571-z
• 发表时间: 2017-09-05
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Larrimore KE;Kazan IC;Kannan L;Kendle RP;Jamal T;Barcus M;Bolia A;Brimijoin S;Zhan CG;Ozkan SB;Mor TS
• 通讯作者: Mor TS

Physiological roles for butyrylcholinesterase: A BChE-ghrelin axis.

• DOI: 10.1016/j.cbi.2016.02.013
• 发表时间: 2016-11-25
• 期刊: Chemico-biological interactions
• 影响因子: 5.1
• 作者: Brimijoin S;Chen VP;Pang YP;Geng L;Gao Y
• 通讯作者: Gao Y