Definitive Preclinical Studies of Hydrolase Gene Transfer to Treat Cocaine Abuse

项目总结 这项研究的最终目标将是FDA允许进行一项首例人类临床试验 基因疗法，以帮助寻求治疗的可卡因使用者成为和保持戒断。的基础是 治疗是一种病毒介导的正常血浆酶的基因转移，这种酶能够将可卡因代谢成 无害的副产物被活性部位的5个点突变大大增强。累积数据 来自研究人员实验室的研究表明，这样的治疗应该在减少可卡因方面有效 奖励价值到了即使是强迫症使用者也不会有动力继续服药的地步。一个 在对小鼠、大鼠和恒河猴的同一系列研究中获得的广泛的毒理学和病理学数据 猴子没有表现出不良反应。这些数据最近在前IND中提交给FDA 打包并在与没有提出明确反对意见的机构人员举行的“Pre-Pre-IND”电话会议上进行讨论 拟议中的人体试验。然而，FDA要求提供新的数据，并对载体进行关键研究的重复 按照“良好实验室操作规范”(GLP)标准生产。本提案寻求资金，以收购 需要(大量)载体，以便以专业质量开展明确的临床前研究 保证(QA)。此外，我们致力于为初步的人体研究铺平道路， 最终试剂，由贝勒医学院的汤姆·牛顿和汤姆·科斯滕博士进行。因此，所有 资金将用于测试一种有前景的新成瘾疗法，并将其带入临床 申请。

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.