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: 8705482
• 负责人: WILLIAM Stephen BRIMIJOIN
• 金额: $ 76.48万
• 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/8705482
• 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且安全的新型生物治疗方法来治疗可卡因滥用，并使这种治疗方法达到适合临床试验的程度。将采用的方法利用基因转移载体来传递突变版本的人血浆丁酰胆碱酯酶（BChE），该酶可以有效地将可卡因水解成基本上没有毒性和奖励潜力的代谢物。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，同时还能减少自我给药的奖赏刺激，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类灵长类动物，并将扩大与可卡因水解酶作为注射蛋白直接递送和通过基因转移载体递送时的安全性相关的观察范围和细节。治疗效果的性质和程度也将使用一系列药代动力学和行为模型比以前更详细地进行检查。在进一步完善用于载体驱动的体内转导的酶编码序列之后，还将关注在严格控制的条件下以足够的数量生产最佳有效载体以最终用于人类的问题。