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

描述（由申请人提供）：本竞争性修订是根据编号no - od -09-058的通知提交的，题为“NIH宣布竞争性修订申请的恢复法案资金可用性”。目前提交的文件修改了一项与治疗可卡因滥用的新概念有关的家长补助金，该概念设想在可卡因进入大脑的途中拦截可卡因作为减少寻求毒品行为的一种手段。父母资助研究了用强效可卡因水解酶（CocH）实现这一目标的可能性。修订建议扩大努力，增加人员，以处理水解酶与抗可卡因疫苗的协同组合将大大增加这种药物拦截战略的治疗能力这一非常有希望的潜力。该计划建立在父母资助下的成功成果的基础上，该成果表明，可卡因水解酶将拯救过量致死的大鼠，并防止在成瘾复发的大鼠模型中恢复寻求可卡因的行为。我们的观察结果进一步支持了这一点，即通过使用耐受性良好的新一代辅助性病毒载体进行基因转移，在啮齿类动物中几乎可以无限期地维持治疗水平的CocH而没有伤害的证据。对CocH的研究将继续有增无减，重点关注CocH影响可卡因滥用各个阶段的能力，包括获得、维持、消失和恢复。我们还将继续努力优化长期递送有效酶水平的方法，包括系统递送修饰的成体干细胞。然而，对研究计划的主要修改是一个新的目标，即深入探索在酶递送的基础上添加抗可卡因抗体或可卡因疫苗的效果。初步结果已经表明，这种情况可能比单独使用任何一种药物更能降低大脑中的药物浓度。数据还表明，CocH继续清除血液中的可卡因，并能够在几分钟内“卸载”和破坏抗体结合的药物。这种效果应该使该系统能够处理在短时间内反复递送的大剂量可卡因。这些考虑使我们提出了一个主要假设，即对接种疫苗或被动免疫的受试者施用可卡因水解酶将具有前所未有的力量，使寻求药物的行为完全和持久地消失。

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.