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 这项研究将以FDA许可的最终目的进行，以进行人类的首次人类临床试验 基因疗法以帮助寻求治疗的可卡因使用者成为戒酒。的基础 治疗是一种正常血浆酶的病毒介导的基因转移，其能力将可卡因代谢 无害的副产品在活跃部位中的5个点突变大大增强。累积数据 从研究人员的实验室中表明，这种治疗应有效减少可卡因 奖励价值到即使是强迫用户也将不再有动力继续服用该药物的程度。 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数据范围 猴子没有表现出不利影响。这些数据最近以预先指示提交给FDA 包装并在“预先印度的电话会议”中与没有提出坚定对象的机构人员进行讨论 提议的人类审判。但是，FDA要求使用矢量进行新数据和重复关键研究 根据“良好的实验实践”（GLP）标准生产。本提案寻求资金来获取 需要（大量）以专业质量进行的确定临床前研究的矢量 保证（QA）。此外，我们致力于通过经过验证的人类研究铺平道路 最终试剂，由Drs进行。贝勒医学院的汤姆·牛顿和汤姆·科斯顿。一切 资金将用于测试有希望的新添加疗法，并将其延伸到临床上 应用。

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