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.

摘要 酒精使用障碍（AUD）是一种慢性疾病，其特征是强迫性酒精使用， 控制酒精的使用，以及不使用酒精时的负面情绪状态， 与一系列医疗、心理、社会、经济和个人问题有关。AUD是 全球性和普遍性;在对美国36，000多名成年人的调查中，AUD的12个月患病率为 13.9%，2015年影响了美国超过4400万成年人。美国的总经济成本是 估计每年2500 - 3000亿美元。澳元经常得不到治疗，部分原因可能是缺乏 充足的治疗选择;据估计，符合AUD标准的美国成年人中<10% 寻求帮助或治疗，同样低比例的AUD治疗接受 药物治疗.对于AUD的有效治疗存在大量未满足的医疗需求。那里 有三种FDA批准的治疗AUD的药物：双硫仑，口服和长效注射纳洛酮， 和阿坎酸;然而，许多个体对这些表现出有限的反应或没有反应， 合规是一个因素。Dicerna正在开发一种siRNA来沉默肝脏中的ALDH 2基因表达 （DCR-ALDH 2）作为AUD的治疗。DCR-ALDH 2已得到全面优化，并且效果显著 在体外以及在完整小鼠和猴的肝脏中降低ALDH 2，并在 小鼠酗酒模型。该项目的目标是通过IND- 为AUD的研究和早期临床试验提供了条件。在U44中，我们提出了第一阶段的五个目标， 第二阶段的三个目标。在SBIR I期，我们建议合成非cGMP原料药， 探索性研究，开发下游活动的相关测定，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。这些活动应导致 与FDA的IND前会议。在SBIR第二阶段，我们将合成cGMP批次的药物，并进行 在小鼠和NHP中进行IND启用毒理学研究。在成功实现这些目标后，我们将 开始I期临床试验。我们的主要结局指标是安全性， 不良事件或严重不良事件的发生。我们的次要结局指标包括 药物PK/PD，以及乙醇给药后药物对乙醛水平的影响。Dicerna 预期通过长效、特异性药物对AUD治疗产生重大影响 几乎没有副作用，这将提高患者的依从性。