Development of a Human Hydrolase to Treat Cocaine Abuse and Overdose:Rat Models

描述(由申请人提供)：本竞争性修订是针对编号为NOT-OD-09-058的通知提交的，标题为“NIH宣布恢复法资金可用于竞争性修订申请”。目前提交的文件修改了一项涉及治疗可卡因滥用的新概念的父母拨款，该概念设想在通往大脑的途中拦截可卡因，以此作为减少寻求毒品行为的一种手段。家长赠款调查了使用强大的可卡因水解酶(COCH)实现这一目标的可能性。修订建议扩大努力，增加人员，以解决非常有希望的潜力，即水解酶与反可卡因疫苗的协同组合将极大地提高这种药物拦截战略的治疗能力。该计划建立在父母赠款下的努力的成功结果的基础上，该努力表明，可卡因水解酶将把大鼠从致命的过量服药中拯救出来，并防止在成瘾复发的大鼠模型中恢复寻找可卡因的行为。我们的观察进一步支持，通过使用耐受性良好的新一代依赖助手的病毒载体进行基因转移，可以在啮齿动物身上几乎无限期地维持COCH的治疗水平，而没有伤害的证据。Coch的研究将继续有增无减，重点是Coch影响可卡因滥用的所有阶段的能力，包括获得、维持、灭绝和恢复。还将继续努力优化长期输送有效酶水平的方法，包括系统输送改良的成体干细胞。然而，对研究计划的主要修订是一个新的目标，即深入探索在酶传递的基础上添加抗可卡因抗体或可卡因疫苗的影响。已经获得的初步结果表明，与单独使用这两种药物相比，这种条件可能会更大程度地降低大脑中的药物浓度。数据还表明，可卡因继续从血液中清除可卡因，并能够在几分钟内“卸载”并摧毁抗体结合的药物。这种效果应该会使系统做好准备，以处理短时间内重复注射的大剂量可卡因。这些考虑导致了我们的主要假设，即给接种疫苗或被动免疫的受试者注射可卡因水解酶将具有前所未有的力量，将寻求毒品的行为彻底和持久地消灭。 与公共健康相关：蛋白质工程的最新进展导致了一种人类酶，它可以足够快地摧毁可卡因，防止它到达心脏或大脑。我们的初步结果表明，这种酶可以将大鼠从药物过量后的致命性癫痫发作中拯救出来，并还可以防止以前成瘾的大鼠在获得可卡因后复发。父母拨款的目的是研究这种酶的直接治疗或基因治疗是否可以减少作为人类可卡因成瘾模型的大鼠的寻药行为。竞争性修订要求支持一项新的目标，该目标旨在通过酶治疗与抗可卡因疫苗的协同组合，在抑制药物寻找行为的力量和持续时间方面取得显著进展的潜力。

DESCRIPTION (provided by applicant): This competitive revision is submitted in response to Notice Number NOT-OD-09-058, entitled "NIH Announces the Availability of Recovery Act Funds for competitive Revision Applications". The current submission modifies a parent grant concerned with a novel concept for treatment of cocaine abuse that envisages interception of cocaine en route to brain as a means of reducing drug-seeking behavior. The parent grant investigates the potential to accomplish that goal with a powerful cocaine hydrolase (CocH). The revision proposes an expanded effort, with additional personnel, to address the very promising potential that synergistic combinations of hydrolase with anti-cocaine vaccine will dramatically increase the therapeutic power of such a drug-interception strategy. The plan builds on the successful outcome of efforts under the parent grant, which showed that cocaine hydrolase will rescue rats from lethal overdose and prevent reinstatement of cocaine-seeking behavior in a rat model of addiction relapse. It is further supported by our observations that therapeutic levels of CocH can be maintained almost indefinitely in rodents without evidence of harm, using gene transfer with a well-tolerated, new-generation, helper- dependent viral vector. Research with CocH will continue unabated, focusing on the ability of CocH to affect all phases of cocaine abuse, including acquisition, maintenance, extinction, and reinstatement. Efforts will also be continued to optimize methods for long-term delivery of effective enzyme levels, including the systemic delivery of modified adult stem cells. The major revision to the research plan, however, is a new aim to explore in depth the effects of adding anti-cocaine antibody or cocaine vaccine on top of enzyme delivery. Preliminary results have already been obtained showing that such conditions are likely to reduce brain concentrations of drug more than is possible with either agent alone. The data also indicate that CocH continues to clear cocaine from the blood stream and is capable of "offloading" and destroying antibody bound drug within minutes. That effect should prepare the system to handle large doses of cocaine repeatedly delivered over short intervals of time. These considerations lead us to the major hypothesis that the administration of cocaine hydrolase to vaccinated or passively immunized subjects will have unprecedented power to drive drug-seeking behavior into complete and lasting extinction. PUBLIC HEALTH RELEVANCE: Recent advances in protein engineering have led to a human enzyme that destroys cocaine rapidly enough to prevent it from reaching the heart or brain. Our preliminary results show that this enzyme rescues rats from lethal seizures after drug overdose and also prevents formerly addicted rats from relapsing when they get access to cocaine. The parent grant is aimed at investigating whether direct treatment or gene therapy with this enzyme can reduce drug-seeking behavior in rats as a model for cocaine addiction in humans. The competitive revision requests support for a new aim which addresses the potential for dramatic gains in the power and duration of suppressing drug-seeking behavior by a synergistic combination of enzyme treatment with an anti-cocaine vaccine.