Pre-clinical Testing of a Novel Therapeutic for Nonalcoholic Steatohepatitis

非酒精性脂肪性肝炎新疗法的临床前测试

• 批准号: 9386379
• 负责人: Joel Thomas Dudley
• 金额: $ 33.85万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-18 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9386379
• 关键词: Affect; Algorithms; Animal Model; Area; Cells; Cholesterol; Cirrhosis; Clinic; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; Communication; Complex; Data; Development; Diet; Disease; Disease model; Documentation; Environment; Epidemic; Fatty acid glycerol esters; Fibrosis; Functional disorder; Gastroesophageal reflux disease; Gene Expression; Genetic Transcription; Genomics; Goals; Grant; Health; Hepatic; Hepatic Stellate Cell; Hepatitis C; Hereditary Disease; Histologic; Human; Immune; In Vitro; Incentives; Incidence; Industry; Inflammation; Injury; Liver; Liver Failure; Liver diseases; Medical; Metabolic; Modeling; Molecular; Mus; Obesity; Pathogenesis; Pathway interactions; Patient Recruitments; Patients; Pharmaceutical Preparations; Pharmacy (field); Phase; Physiological; Play; Population; Preparation; Primary Malignant Neoplasm of Liver; Procedures; Progressive Disease; Protocols documentation; Recruitment Activity; Research Design; Research Personnel; Resources; Risk; Role; Safety; Site; Testing; Therapeutic; TimeLine; United States; Work; base; clinical efficacy; drug development; drug discovery; efficacy study; efficacy testing; efficacy trial; experience; experimental study; gastrointestinal; genome-wide; in vivo; industry partner; innovation; liver transplantation; mouse model; multidisciplinary; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; novel therapeutics; pre-clinical; preclinical study; prevent; research clinical testing; safety testing; therapeutic development; trial design

PROJECT SUMMARY Nonalcoholic steatohepatitis, or NASH, is a serious and escalating health threat in the United States, affecting at least 2-5% of the population, with a rising incidence paralleling the obesity epidemic. There are no effective medical treatments. NASH is a “silent” liver disease characterized by hepatic accumulation of fat accompanied by inflammation and hepatocellular injury (“ballooning”). NASH is a progressive disease that can culminate in cirrhosis and a heightened risk of primary liver cancer. It is the second leading cause of liver failure and will supplant hepatitis C as the primary indication for liver transplantation by 2020. The accelerating impact of NASH underscores the urgent need to develop novel therapies that prevent progression or, in advanced stages, reverses inflammation, injury and fibrosis. Drug repurposing is an attractive approach to identify novel therapeutics for NASH because it can greatly shorten the drug development timeline. To exploit new computational strategies to uncover relevant repurposed drugs we applied a chemogenomic drug repurposing algorithm in collaboration with AstraZeneca, to identify novel indications for a set of AstraZeneca compounds that previously failed human efficacy studies for various indications apart from safety concerns. Our analysis identified a specific compound that previously failed efficacy trials for a gastrointestinal indication as a drug repurposing candidate for NASH. The compound's mechanism of action would be considered quite novel for treating NASH, and NASH would represent a leap to a completely new disease area compared to the compound's original indication. In the UH2 phase of this grant we propose to perform in vitro and in vivo pre- clinical studies to evaluate the efficacy of the repurposed compound for treating NASH. We will achieve this goal through the following aims: Aim 1) Experimentally validate molecular engagement of a novel drug repurposing candidate for NASH. Aim 2) Evaluate the efficacy of a novel drug repurposing candidate for NASH using a murine model of disease. If the milestones from the UH2 phase are successfully achieved and a “go” decision point is reached, we will use the UH3 phase of the grant to plan a phase 2a clinical trial. We have assembled a multidisciplinary team with demonstrated expertise in liver disease, drug repurposing, genomics, basic and clinical analysis of liver disease, clinical trials, and pharmaceutic drug development. The team capabilities and expertise along with the established collaboration between Mount Sinai and AstraZeneca provide a seamless path to move from pre-clinical studies directly to human clinical trials.

项目摘要 非酒精性脂肪性肝炎（NASH）是美国一种严重且不断升级的健康威胁， 至少占人口的2-5%，随着肥胖症的流行，发病率也在上升。没有有效 医学治疗NASH是一种“无症状”肝脏疾病，其特征在于肝脏脂肪积聚， 炎症和肝细胞损伤（“气球样变”）。NASH是一种进行性疾病，其可最终导致 肝硬化和原发性肝癌的风险增加。它是肝衰竭的第二大原因， 到2020年取代丙型肝炎成为肝移植的主要适应症。加速的影响 NASH强调迫切需要开发新的治疗方法，以防止进展，或在先进的 分期，逆转炎症，损伤和纤维化。药物再利用是一种有吸引力的方法，以确定新的 这是NASH的最佳治疗剂，因为它可以大大缩短药物开发时间轴。开拓新 为了发现相关的再利用药物，我们应用了化学基因组药物再利用 与阿斯利康合作的算法，以确定一组阿斯利康化合物的新适应症 除了安全性问题之外，以前失败的各种适应症的人体功效研究。我们的分析 确定了一种特定的化合物，这种化合物以前在胃肠道适应症的疗效试验中失败， 重新利用NASH的候选人。该化合物的作用机制将被认为是相当新颖的， 治疗NASH，与治疗NASH相比，NASH将代表一个全新疾病领域的飞跃。 化合物的原始指示。在UH 2阶段，我们建议进行体外和体内预处理， 临床研究，以评估重新利用的化合物用于治疗NASH的功效。我们将实现这一目标 通过以下目标实现目标：目标1）实验验证新药的分子参与 重新利用NASH的候选人。目的2）评价一种新的药物再利用候选药物治疗NASH的疗效 使用的是一种鼠疾病模型。如果UH 2阶段的里程碑成功实现， 一旦达到决策点，我们将使用UH 3期赠款计划2a期临床试验。我们有 组建了一个多学科团队，在肝病，药物再利用，基因组学， 肝病的基础和临床分析、临床试验和药物开发。球队 能力和专业知识沿着西奈山和阿斯利康之间建立的合作 提供了一条从临床前研究直接进入人体临床试验的无缝路径。