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

开发针对酒精使用障碍的 ALDH2 靶向 RNAi 疗法

• 批准号: 10241554
• 负责人: Bob D. Brown
• 金额: $ 150万
• 依托单位: DICERNA PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241554
• 关键词: Acetaldehyde; Adult; Adverse event; Affect; Alcohol consumption; Alcohols; Animals; Antibodies; Behavior Therapy; Binding Proteins; Biodistribution; Biological Assay; Chronic; Clinical Trials; Cyclic GMP; Development; Disease; Disulfiram; Documentation; Dose; Drug Interactions; Drug Kinetics; Economics; Enzymes; Ethanol; Ethanol Metabolism; FDA approved; Gene Expression; Genes; Goals; Headache; Hepatocyte; Human; In Vitro; Individual; Injectable; Lead; Liver; Measurement; Medical; Messenger RNA; Metabolism; Modeling; Monkeys; Mus; Naltrexone; National Institute on Alcohol Abuse and Alcoholism; Nausea; Oral; Outcome Measure; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Placebos; Preparation; Prevalence; Process; RNA Interference; RNA Interference Therapy; Randomized; Reagent; Reporting; Safety; Serious Adverse Event; Serum; Serum Proteins; Single-Blind Study; Small Business Innovation Research Grant; Small Interfering RNA; Source; Surveys; Testing; Toxicokinetics; Toxicology; Validation; acamprosate; alcohol abuse therapy; alcohol use disorder; aldehyde dehydrogenases; arm; assay development; binge drinking; clinical development; compliance behavior; cost; design; drinking; drug development; economic cost; effective therapy; healthy volunteer; help-seeking behavior; improved; knock-down; medication safety; meetings; negative emotional state; non-compliance; nonhuman primate; phosphoramidite; pre-clinical; primary outcome; psychologic; research clinical testing; response; secondary outcome; side effect; small molecule inhibitor; social; statistics; success; trend

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.

抽象的 酒精使用障碍（AUD）是一种慢性疾病，其特征是强迫饮酒，丢失 控制酒精的使用以及不使用酒精时的负面情绪状态 与一系列医学，心理，社会，经济和个人问题有关。 aud是 全球和普遍；在美国36,000多名成年人的调查中，AUD患有12个月的患病率 13.9％，2015年美国影响超过4400万成年人。美国的总经济成本是 估计每年2500亿美元。 aud通常不加以治疗，可能部分是由于缺乏 足够的治疗选择；据估计，符合AUD标准的美国成年人中<10％ 寻求帮助或治疗 药物治疗。有很大的未满足医疗需求对AUD进行有效治疗。那里 是AUD的三种FDA批准的药物：二硫仑，口服和长效注射纳曲酮， 和Acamprosate；但是，许多人对此表示有限或没有反应，而差 合规性一个因素。 Dicerna正在开发siRNA，以使肝脏中的ALDH2基因表达沉默 （dcr-aldH2）作为AUD的治疗方法。 DCR-ALDH2已完全优化，并且显着 在完整的小鼠和猴子中降低体外和肝脏中的ALDH2，并在A中证明了功效 鼠标暴饮暴食模型。该项目的目的是通过ind-促进dcr-aldh2 启用研究和AUD的早期临床测试。在此U44中，我们在第一阶段提出了五个目标，以及 第二阶段的三个目标。在SBIR I期，我们建议合成非CGMP药物的药物 探索性研究，开发下游活动的相关测定法，并执行剂量范围 查找PK/PD研究并查看小鼠和NHP的生物分布。这些活动应该导致 与FDA的预定会议。在SBIR II期中，我们将合成CGMP的药物和行为 小鼠和NHP中的毒理学研究。在这些目标成功之后，我们将 开始I期临床试验。我们的主要结果指标是安全，如 发生不良事件或严重的不良事件。我们的次要结果措施包括 药物PK/PD，以及药物对乙醇施用后对乙醛水平的影响。迪切纳 预计通过使用长效，特定的药物对AUD的治疗产生重大影响 很少有副作用可以提高患者依从性。