Development of novel pharmacotherapies for AUD

AUD 新型药物疗法的开发

• 批准号: 10382131
• 负责人: Ethan Michael Anderson
• 金额: $ 39.29万
• 依托单位: NEUROEPIGENIX, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10382131
• 关键词: Acoustics; Adult; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Behavior; Behavioral; Biological Assay; Biological Availability; Body Weight decreased; Brain; Chronic; Clinical; Data; Dependence; Development; Disease model; Dose; Drug Kinetics; Economic Burden; Environment; Enzyme Inhibitor Drugs; Enzymes; Epigenetic Process; Ethanol dependence; FDA approved; Female; Funding; Future; Goals; Half-Life; Heavy Drinking; Human; Individual; Injections; Investigational Drugs; Investigational New Drug Application; Lead; Legal patent; Letters; Maximum Tolerated Dose; Measurement; Measures; Methods; Modeling; Motor Activity; Mouse Strains; Mus; Opioid agonist; Oral; Patients; Penetrance; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pre-Clinical Model; Relapse; Route; Self Administration; Side; Small Business Technology Transfer Research; Societies; Stress; Sucrose; Swimming; System; Testing; Therapeutic; Toxic effect; addiction; alcohol abuse therapy; alcohol exposure; alcohol use disorder; conditioned fear; drinking; drug development; effective therapy; inhibitor; innovation; intraperitoneal; kappa opioid receptors; male; novel; patient population; phase 2 study; pre-clinical; preventable death; screening; treatment duration

Project Summary The overall goal of this proposal is to characterize a lead compound with a novel mode of action (MOA) that reduces both stress- and dependence-related alcohol drinking in a preclinical model of Alcohol Use Disorder (AUD). AUD is a major problem in the U.S. as approximately 13.9% of adults meet AUD criteria per year. The annual economic burden of AUD is estimated at >$200 billion and AUD is a leading cause of preventable deaths in the USA. Persistent alcohol abuse and dependence is difficult to treat in part because alcohol increases the reactivity of the body’s stress systems. The influence of stress systems facilitates the “the dark side of addiction”, and stress is a primary factor that triggers relapse. Therefore, pharmacotherapies that can reduce stress- and dependence-associated alcohol drinking could reduce both heavy drinking and stress-triggered relapse in individuals suffering from AUD. We recently discovered that systemic administration of an epigenetic enzyme inhibitor reduced both stress- and dependence-potentiated alcohol drinking in a preclinical model. We have filed for patent protection of this entirely novel MOA to treat AUD, which provides a commercial path forward. In this Phase I STTR application, we will evaluate oral bioavailability of our lead compound to examine whether the preferred oral method of delivery is feasible for AUD treatment. We will also examine maximum tolerated dose (MTD) and behavioral toxicity measures. We will then determine optimal dosing conditions, and we seek to establish strong proof-of-principle data that these compounds reduce dependence- and stress-related alcohol drinking in multiple preclinical models and multiple mouse strains in both male and female mice. At the conclusion of these aims, we expect to have sufficient pre-clinical information for subsequent Phase II STTR studies targeting a future Investigational New Drug (IND) application.

项目摘要 该提案的总体目标是用一种新颖的作用方式（MOA）表征铅化合物（MOA） 在酒精使用障碍的临床前模型中，减少应力和依赖相关的饮酒 （aud）。在美国，AUD是一个主要问题，因为大约13.9％的成年人每年符合AUD标准。这 AUD的年度经济燃烧估计为2000亿美元，AUD是可预防死亡的主要原因 在美国。持续的酒精滥用和依赖性很难部分，因为酒精会增加 人体压力系统的反应性。压力系统的影响促进了“成瘾的阴暗面”， 压力是触发释放的主要因素。因此，可以减少应力和 依赖性相关的饮酒可以减少大量饮酒和压力触发的缓解 患有aud的人。我们最近发现，系统施用表观遗传酶 在临床前模型中，抑制剂降低了应力和依赖性抑制性饮酒。我们已提交 为了保护这种完全新颖的MOA来治疗AUD，这提供了商业道路。在这个 I期STTR应用程序，我们将评估铅化合物的口服生物利用度，以检查是否是否 首选的口服交付方法对于AUD治疗是可行的。我们还将检查最大耐受剂量 （MTD）和行为毒性指标。然后，我们将确定最佳给药条件，我们试图 建立有力的原理证明数据，这些化合物减少依赖性和压力相关的酒精 在多种临床前模型中饮用，男性和雌性小鼠的多种小鼠菌株。结论 在这些目标中，我们希望有足够的临床前信息进行随后的II期STTR研究 针对未来的研究新药（IND）应用。