Development of an ALDH2-Targeting RNAi Therapeutic for Alcohol Use Disorders

摘要 酒精使用障碍(AUD)是一种慢性疾病，其特征是强迫性饮酒、丧失 对酒精使用的控制，以及在不饮酒时的负面情绪状态 与一系列的医疗、心理、社会、经济和个人问题有关。澳元是 在全球范围内流行；在一项对美国36,000多名成年人的调查中，AUD的患病率为12个月 13.9%，2015年美国有超过4400万成年人受到影响。美国的总经济成本是 估计每年2,500-3,000亿美元。澳元经常得不到治疗，部分原因可能是缺乏 适当的治疗选择；据估计，符合澳元病标准的美国成年人中有10% 寻求帮助或治疗，而接受AUD治疗患者中获得帮助或治疗的比例也同样较低 药物疗法。对澳门氏症的有效治疗存在大量未得到满足的医疗需求。那里 有三种FDA批准的治疗AUD的药物：双硫兰、口服和长效注射用纳曲酮， 和无菌胺；然而，许多人对这些反应有限或没有反应， 合规是一个因素。Dicerna正在开发一种siRNA来沉默肝脏中ALDH2基因的表达 (DCR-ALDH2)作为AUD的治疗。DCR-ALDH2已经过全面优化，并且显著 在体外和完整小鼠和猴子的肝脏中降低ALDH2，并在 小鼠狂饮模型。该项目的目标是通过IND-ALDH2推进DCR-ALDH2。 使澳大利亚的研究和早期临床测试成为可能。在这份U44中，我们提出了第一阶段的五个目标，以及 第二阶段的三个目标。在SBIR第一阶段，我们建议合成非cGMP药物物质 探索性研究，开发下游活动的相关分析，并进行剂量范围 寻找PK/PD研究，并观察小鼠和NHP中的生物分布。这些活动应该导致 IND前与FDA的会议。在SBIR第二阶段，我们将合成大量的cGMP药物和传导 在小鼠和NHP中进行的IND毒理学研究。在实现这些目标之后，我们将 开始一期临床试验。我们的主要结果衡量标准是安全性，如以下评估 不良事件或严重不良事件的发生。我们的次要结果衡量标准包括 药物PK/PD，以及给药后药物对乙醛水平的影响。Dicerna 预期通过拥有一种长效、特异的药物对AUD的治疗产生重大影响 几乎没有副作用，可以改善患者的依从性。

Abstract Alcohol Use Disorder (AUD) is a chronic condition characterized by compulsive alcohol use, loss of control over alcohol use, and a negative emotional state when not using alcohol, with such use associated with a range of medical, psychological, social, economic, and personal problems. AUD is global and prevalent; in a survey of over 36,000 adults in the US, AUD had a 12-month prevalence of 13.9%, affecting over 44 million adults in the US in 2015. The total economic cost in the US is estimated at $250-300 billion per year. AUD often goes untreated, possibly partly due to the lack of adequate treatment options; it is estimated that <10% of US adults who meet the criteria for AUD seek help or treatment, and that similarly low percentages of those treated for AUD receive pharmacotherapy. There exists a large unmet medical need for effective treatments for AUD. There are three FDA-approved medications for AUD: disulfiram, oral and long-acting injectable naltrexone, and acamprosate; however, many individuals show limited or no response to these, with poor compliance a factor. Dicerna is developing an siRNA to silence ALDH2 gene expression in liver (DCR-ALDH2) as a treatment for AUD. DCR-ALDH2 has been fully optimized, and significantly reduces ALDH2 in vitro and in liver in intact mice and monkeys, and demonstrated efficacy in a mouse binge drinking model. The goal of this project is to advance DCR-ALDH2 through IND- enabling studies and early clinical testing for AUD. In this U44, we propose five Aims in Phase I, and three Aims in Phase II. In SBIR Phase I, we propose to synthesize non-cGMP drug substance for exploratory studies, develop the relevant assays for downstream activities, and perform dose-range finding PK/PD studies and look at biodistribution in mice and NHPs. These activities should lead to a pre-IND meeting with FDA. In SBIR Phase II, we will synthesize the cGMP lot of drug and conduct IND-enabling toxicology studies in mouse and NHP. Following success with these aims, we will commence a Phase I clinical trial. Our primary outcome measure is safety, as evaluated by occurrence of adverse events or serious adverse events. Our secondary outcome measures include drug PK/PD, and effect of drug on acetaldehyde levels after ethanol administration. Dicerna anticipates having a significant impact on the treatment of AUD by having a long-acting, specific drug with few to no side effects that will improve patient compliance.