Cocaine hydrolase gene therapy for cocaine abuse (DPI)

描述（由申请人提供）：本项目的目标是尽快向前发展，开发一种有效和安全的新的可卡因滥用生物治疗方法，并将这种治疗方法带到临床试验的适当阶段。将采用的方法利用基因转移载体来递送突变形式的人血浆丁酰胆碱酯酶（BChE），其有效地将可卡因水解成在很大程度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，同时也减少了自我给药药物的奖励刺激，并拮抗药物引发的药物寻求行为的恢复。拟议的工作将扩展到包括非人灵长类动物，并将扩大范围和细节的观察有关的可卡因水解酶的安全性时，直接提供注射的蛋白质和基因转移载体时提供。还将使用一系列药代动力学和行为模型，比以前更详细地检查治疗效果的性质和幅度。在进一步改进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量产生最佳有效载体以最终用于人类的问题。 公共卫生相关性：拟议工作的实际成果应当令人信服地证明，用可卡因破坏酶进行基因治疗，对于治疗那些试图戒毒并保持这种状态的可卡因使用者来说，是一种现实的前景。如果该项目成功，它将表明这种治疗在实验动物中是安全有效的，并将产生符合人类使用标准的试剂。 关于评分的管理说明：所有NIDA翻译先锋奖（DP1）申请者都是

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. PUBLIC HEALTH RELEVANCE: The practical outcome of the proposed work should be a convincing demonstration that gene therapy with a cocaine-destroying enzyme is a realistic prospect for treating cocaine users who are trying to become drug free and remain that way. If the project is successful, it will have shown that such a treatment is safe and effective in experimental animals and it will generate reagents that meet standards for use in humans. ADMINISTRATIVE NOTE ON SCORING: All NIDA Translational Avant Garde Award (DP1) applicants are e