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: 10000864
• 负责人: WILLIAM Stephen BRIMIJOIN
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000864
• 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.

项目概要 这项研究的最终目标是获得 FDA 批准对一种药物进行首次人体临床试验。 基因疗法帮助寻求治疗的可卡因使用者戒除并保持戒断。的基础 疗法是病毒介导的正常血浆酶的基因转移，该酶能够将可卡因代谢成可卡因 活性位点的 5 个点突变大大增强了无害副产品的性能。累计数据 研究人员实验室的结果表明这种治疗应该能有效减少可卡因 奖励价值达到即使是强迫性使用者也会大大降低继续服用药物的动力的程度。一个 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不良影响。这些数据最近在预 IND 提交给 FDA 并在“IND 前电话会议”中与机构人员进行讨论，他们没有提出坚决反对意见 到拟议的人体试验。然而，FDA 要求提供新数据并重复针对载体的关键研究 根据“良好实验室实践”（GLP）标准生产。本提案寻求资金来收购 以专业质量进行明确的临床前研究所需（大量）载体 保证（QA）。此外，我们致力于通过经过验证的初步人体研究铺平道路 最终试剂，由博士进行。贝勒医学院的汤姆·牛顿和汤姆·科斯滕。因此所有 资金将用于测试一种有前途的新成瘾疗法，并将其跨入临床门槛 应用。