Cocaine hydrolase gene therapy for cocaine abuse (DPI)

描述(由申请人提供)：该项目的目标是在开发一种有效和安全的新的可卡因滥用生物治疗方法方面尽快取得进展，并使这种治疗方法达到适合临床试验的程度。将采取的方法利用基因转移载体来传递人血浆丁酰胆碱酯酶(BChE)的突变版本，这种酶能有效地将可卡因水解成基本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中毒，同时还可以减少自我给药的奖励刺激，并拮抗药物诱导的药物寻找行为的恢复。拟议的工作将扩大到包括非人类灵长类动物，并将扩大与可卡因水解酶的安全性有关的观察范围和细节，当可卡因水解酶直接作为注射蛋白输送和通过基因转移载体输送时。治疗效果的性质和程度也将比以前更详细地检查，使用一系列药代动力学和行为模型。在进一步完善体内载体驱动转导的酶编码序列后，还将注意在严格控制的条件下生产足够量的最佳有效载体的问题，以便最终用于人类。 与公共健康相关：拟议工作的实际结果应该是一个令人信服的证明，即使用可卡因破坏酶进行基因治疗是治疗试图戒毒并保持这种状态的可卡因吸毒者的现实前景。如果该项目成功，它将表明这种治疗方法在实验动物中是安全有效的，它将产生符合人类使用标准的试剂。 评分管理说明：所有NIDA翻译先锋奖(DP1)申请者均为e

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