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。尽管积极研究和开发用于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酒。这一严酷的现实清楚地表明，90%以上的酗酒者在治疗开始后的四年内至少复发一次。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式;一种位点特异性靶向神经再生过程，逆转与依赖相关的奖励途径功能缺陷，避免依赖长期患者依从性，并在引入后表现出永久性效果。我们认为，基因治疗，最终在过度表达胶质源性神经营养因子（GDNF）的腹侧被盖区（VTA），奖励神经回路的关键组成部分，是这样一个治疗范例。在啮齿类动物中进行的初步研究表明，腹侧被盖区内GDNF的表达升高阻断了未处理动物中饮酒的升级，并显著减弱了酒精经验丰富的动物中的过度饮酒，而抑制腹侧被盖区中的内源性GDNF增强了重度饮酒的进展。推进这种治疗模式在人类酗酒者中的转化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益处。本项目的目标1将在6个月开放期内在一组雄性食蟹猴中建立重度酒精自我给药。这些方法已经被验证和复制了十多年，猴子发展出类似人类酗酒者的酗酒模式。目的2评价GDNF基因治疗对预防复发和持续大量饮酒的疗效。在1个月的戒断期后，将腺相关病毒血清型2（AAV 2）-GDNF或对照载体双侧输注到每只猴的VTA中，并且将在开放获取条件下重新引入酒精，并且将在多个戒断-复发周期期间监测自我施用模式。我们假设，AAV 2-GDNF治疗将防止复发样饮酒模式，并减少大量饮酒的天数，通过减弱的发生率狂饮（大回合大小），产生醉人的血液酒精浓度。总之，我们相信这将是治疗酗酒的一种变革性方法，也可能适用于治疗其他危及生命的成瘾。如果成功，那么我们的活体数据将包含在向美国食品和药物管理局提交的简报包中，以便通过研究新药（IND）提交来推进这种候选治疗方法，用于未来的临床试验。

 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.