Definitive Preclinical Studies of Hydrolase Gene Transfer to Treat Cocaine Abuse

水解酶基因转移治疗可卡因滥用的明确临床前研究

• 批准号: 10241314
• 负责人: W. Michael Hooten
• 金额: $ 85.38万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241314
• 关键词: Active Sites; Adenovirus Vector; Adenoviruses; Adjuvant; Adverse effects; Affect; Amphetamines; Antibodies; Authorization documentation; Award; Butyrylcholinesterase; Clinical; Clinical Trials; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine Users; Counseling; Data; Dependovirus; Dose; Drug Targeting; Enzymes; Funding; Future; Gene Transfer; Generations; Goals; Health; Human; Human Resources; Hydrolase; Illicit Drugs; Individual; Injections; Investigational Drugs; Investigational Therapies; Journals; Laboratories; Macaca mulatta; Measures; Mediating; Medical; Medicine; Mus; Mutate; National Institute of Drug Abuse; Outcome; Pathology; Peer Review; Pharmaceutical Preparations; Pilot Projects; Plasma; Point Mutation; Problem Solving; Psychotherapy; Publications; Publishing; Rattus; Reagent; Refractory; Research; Research Personnel; Research Project Summaries; Resistance; Rewards; Rodent; Safety; Series; Signal Transduction; Societies; Teleconferences; Testing; Toxicology; United States Food and Drug Administration; Vaccines; Viral Genes; Virus; Work; addiction; clinical application; cocaine overdose; college; cost; design; enzyme activity; falls; first-in-human; gene therapy; human study; immunogenicity; meetings; pre-clinical; preclinical study; psychostimulant; quality assurance; safety study; social; therapy adverse effect; transgene expression; vector

PROJECT SUMMARY This research will be undertaken with the ultimate goal of FDA permission for a First-In-Human clinical trial of a gene therapy to aid treatment-seeking cocaine users in becoming and remaining abstinent. The basis of the therapy is a virus-mediated gene transfer of a normal plasma enzyme whose ability to metabolize cocaine into harmless byproducts has been massively enhanced by 5 point mutations in the active site. Accumulated data from the investigator's laboratory indicates that such a treatment should be effective in reducing cocaine reward value to a point where even a compulsive user will be much less motivated to keep taking the drug. A wide range of toxicology and pathology data acquired in the same series of studies on mice, rats, and rhesus monkeys demonstrated NO adverse effects. These data were recently submitted to the FDA in a pre-IND package and discussed in a “pre-pre-IND teleconference” with Agency personnel who raised no firm objections to the proposed human trial. However FDA requested new data and repetition of key studies with vector produced under “good lab practice” (GLP) standards. The present proposal seeks funding to acquire the needed (large) amounts of vector for definitive preclinical studies carried out with professional quality assurance (QA). In addition, we are committed to paving the way for an initial human study with the validated final reagent, to be carried out by Drs. Tom Newton and Tom Kosten at Baylor College of Medicine. Thus all funds will go towards testing a promising new addiction therapy and carrying it across the threshold to clinical application.

项目摘要 这项研究的最终目标是获得FDA的许可，进行首次人体临床试验， 基因疗法，以帮助寻求治疗的可卡因使用者成为和保持禁欲。的基础 治疗是一种病毒介导的正常血浆酶的基因转移， 无害的副产品已经被活性位点的5个点突变大大增强。累积数据 研究者实验室的结果表明，这种治疗应能有效减少可卡因 奖励价值的一个点，即使是一个强迫用户将大大减少动机继续服用药物。一 在小鼠、大鼠和恒河猴的同一系列研究中获得的广泛毒理学和病理学数据 猴子没有表现出任何副作用。这些数据最近在IND前提交给FDA 包装，并在“IND前电话会议”中与未提出明确反对意见的监管机构人员进行讨论 进行人体试验然而，FDA要求获得新数据并重复使用载体的关键研究 根据“良好实验室实践”（GLP）标准生产。本提案寻求资金，以获得 以专业质量进行确定性临床前研究所需的（大量）载体 保证（QA）。此外，我们致力于为使用经验证的 最终试剂，由贝勒医学院的Tom Newton和Tom Kosten博士进行。因此所有 资金将用于测试一种有前途的新成瘾疗法，并将其推向临床。 应用程序.

项目成果

Cholinesterases and the fine line between poison and remedy.

• DOI: 10.1016/j.bcp.2018.01.044
• 发表时间: 2018-07
• 期刊: Biochemical pharmacology
• 影响因子: 5.8
• 作者: Pope CN;Brimijoin S
• 通讯作者: Brimijoin S