GDNF gene therapy to block relapse of heavy alcohol use in monkeys

 描述(由申请人提供)：酒精中毒和酒精使用障碍是一个主要的公共卫生问题，并与毁灭性的社会和经济负担有关。尽管积极研究和开发治疗酒精中毒的药物疗法，但FDA批准的药物往往不足以维持寻求治疗的个人的长期戒断。90%以上的酗酒者在治疗开始后的四年内至少复发一次，这一事实清楚地表明了这一严峻的现实。该项目的目的是建立一种治疗酒精中毒和酒精使用障碍的新范例；一种特定部位针对神经再生过程的范例，逆转与依赖相关的奖赏途径功能缺陷，避免对长期患者依从性的依赖，并一旦引入就显示出永久的效果。我们认为，在奖赏神经回路的关键组成部分腹侧被盖区(VTA)，最终导致胶质源性神经营养因子(GDNF)过度表达的基因治疗就是这样一种治疗范式。在啮齿动物中进行的初步研究表明，VTA内GDNF的高表达阻止了幼稚动物饮酒的升级，并显著减轻了酗酒动物的过度饮酒，而VTA内源性GDNF的抑制则促进了过度饮酒的进展。推动这种治疗模式在人类酗酒者中的翻译应用的关键下一步是首先证明在非人类灵长类动物(NHP)中进行类似的干预将在降低复发风险方面产生类似的好处。该项目的目标1将在为期6个月的开放访问期内，在一群雄性食蟹猴中建立重酒自我管理。这些方法已经被验证和复制了十多年，猴子形成了类似于在人类酗酒者中观察到的酗酒模式。目的2评价胶质细胞源性神经营养因子基因治疗在预防复发和持续大量饮酒中的作用。在1个月的戒断期后，一种腺相关病毒血清2型(AAV2)-GDNF或对照载体将被注入每只猴子的VTA中，开放获取条件下将重新引入酒精，并将在多个戒断-复发周期中监测自我给药模式。我们假设，AAV2-GDNF治疗将通过减少产生醉人血液酒精浓度的狂欢(大型比赛)的发生率，防止复发的类似饮酒模式，并减少重度饮酒天数。总而言之，我们相信这将是治疗酒精中毒的一种变革性方法，也可能适用于其他威胁生命的成瘾的治疗。如果成功，我们的生活数据将被包括在提交给美国食品和药物管理局的简报中，以便通过研究新药(IND)提交未来的临床测试来推进这一候选治疗方法。

 DESCRIPTION (provided by applicant): Alcoholism and alcohol use disorders represent a major public health problem, and are associated with devastating social and economic burdens. Despite active research and development of pharmacotherapies for the treatment of alcoholism, FDA-approved medications are often insufficient in sustaining long-term abstinence in treatment-seeking individuals. This stark reality is made clear by the fact that upwards of 90% of alcoholics relapse at least once over a four year period following treatment onset. The purpose of this project is to establish a new paradigm for the treatment of alcoholism and alcohol use disorders; one that site- specifically targets a neuro-regenerative process, reverses dependence-associated deficits in reward pathway function, circumvents the reliance on protracted patient compliance, and exhibits a permanent effect once introduced. We believe that gene therapy that culminates in the overexpression of glial-derived neurotrophic factor (GDNF) within the ventral tegmental area (VTA), a key component of the reward neurocircuitry, is such a treatment paradigm. Preliminary work conducted in rodents indicated that elevated expression of intra-VTA GDNF blocks the escalation of alcohol drinking in naive animals and significantly attenuates excessive drinking in alcohol-experienced animals whereas suppression of endogenous GDNF in the VTA enhances the progression to heavy alcohol use. A crucial next step in advancing the translation application of this treatment paradigm to human alcoholics is to first demonstrate that a similar intervention in non-human primates (NHPs) will yield a comparable benefit in reducing relapse risk. Aim 1 of this project will establish heavy alcohol self- administration in a cohort of male cynomolgus monkeys during a 6-month open access period. These methods have been validated and replicated for over a decade, with monkeys developing binge-like drinking patterns of alcohol use that resemble those observed in human alcoholics. Aim 2 will evaluate the efficacy of GDNF gene therapy in preventing relapse and the continuation of heavy drinking. An adeno-associated virus serotype 2 (AAV2)-GDNF or control vector will be bilaterally infused into the VTA of each monkey following a 1-month period of abstinence, and alcohol will be re-introduced under open access conditions and self- administration patterns will be monitored during multiple withdrawal-relapse cycles. We hypothesize that AAV2-GDNF treatment will prevent relapse-like drinking patterns and reduce the number of heavy drinking days by attenuating the incidence of binges (large bout sizes) that produce intoxicating blood alcohol concentrations. In summary, we believe this will be a transformative approach for the treatment of alcoholism that may also be applicable for the treatment of other life-threatening addictions. If successful, then our in-life data will be includd in a briefing package to the U.S. Food & Drug Administration in order to advance this candidate therapeutic through an Investigation New Drug (IND) submission for future clinical testing.