A novel therapy for acute alcoholic hepatitis

急性酒精性肝炎的新疗法

• 批准号: 10604068
• 负责人: Neil McDonnell
• 金额: $ 35.82万
• 依托单位: SEAL ROCK THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10604068
• 关键词: Acute; Acute Alcoholic Hepatitis; Address; Alcoholic Hepatitis; Alcohols; Animal Model; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Bacterial Translocation; Biochemistry; Biological Markers; Blood Circulation; CASP3 gene; CYP2E1 gene; Cardiovascular system; Cells; Cessation of life; Chronic; Clinical; Clinical Trials; Complement; Complex; Conduct Clinical Trials; Cytochrome P450; Data; Diet; Disease; Dose; Dose-Limiting; Enzyme-Linked Immunosorbent Assay; Epithelial; Ethanol; Evaluation; Fibroblasts; Fibrosis; Hepatocyte; Hepatotoxicity; Human; Immune; Immunohistochemistry; Individual; Inflammation; Inflammatory; Injury; Intestinal permeability; Intestines; Liquid substance; Liver; Liver diseases; Lung; Marketing; Mediator of activation protein; Methods; Mitochondria; Modeling; Morbidity - disease rate; Mus; Necrosis; Oxides; Pathology; Patients; Persons; Pharmacology; Pharmacology Study; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Phenotype; Phosphotransferases; Pre-Clinical Model; Prognosis; Property; Rattus; Reactive Oxygen Species; Recovery; Risk; Safety; Series; Serum; Small Business Innovation Research Grant; Stress; Syndrome; Therapeutic; Tight Junctions; Tissues; Toxic effect; Toxicology; alcohol abstinence; cell injury; chronic liver disease; clinically relevant; cytokine; design; dysbiosis; efficacy study; feeding; gut inflammation; improved; in vitro activity; in vivo; inhibitor; liver inflammation; liver injury; microbial; microbiota; mortality; mouse model; nonhuman primate; novel; novel therapeutics; nutrition; preclinical efficacy; response; seal; transcriptome sequencing

Each year approximately 5 million people in the US develop acute alcoholic hepatitis (AH), a syndrome of progressive inflammatory liver injury. In most patients with AH, the illness is mild. However, in patients with severe acute AH, risk of early death is high and intensive management is required with minimal pharmacological agents available. Seal Rock Therapeutics is developing SRT-015, a potent and selective inhibitor of the activated ASK1 kinase to address this unmet need. ASK1 is present in all cells and activated in response to stress factors including reactive oxygen species (ROS), cytokines and LPS. SRT-015 demonstrates direct anti-inflammatory, anti-fibrotic and anti-apoptotic activity in vitro on stimulated human immune cells, fibroblasts and hepatocytes, respectively. SRT-015 treatment was also proven efficacious in vivo using acute and chronic liver disease mouse models and demonstrated safe in GLP toxicology studies. In a Phase 1 clinical trial SRT-015 was well tolerated with no dose-limiting toxicities. SRT-015 is a possible therapeutic for multiple liver diseases including AH. In this SBIR R43, we will conduct IND-enabling efficacy studies of SRT-015 for treatment of severe AH. These studies are designed to determine the minimal efficacious exposure, define clinically relevant biomarkers, and characterize changes in the microbiota and intestinal permeability after SRT-015 treatment in an AH animal model Aim 1: Estimate of minimal efficacious exposure of SRT-015 and efficacy biomarkers in a chronic ethanol plus binge therapeutic AH animal model. We will be using the mouse chronic Lieber-DeCarli ethanol liquid diet (8 weeks) plus binge ethanol model that best reflects human AH disease. The minimum efficacious dose will be identified using three dose levels of SRT-015 treatment administered during the final four weeks of chronic ethanol feeding and biomarkers for fibrosis, inflammation and hepatoxicity evaluated. Aim 2: Evaluation of intestinal permeability, bacterial translocation and intestinal dysbiosis after SRT-015 treatment in a therapeutic AH animal model. To complement and extend the efficacy data, a full characterization of SRT-015 effects on intestinal inflammation and gut barrier function will be conducted. Demonstrating preclinical efficacy of SRT-015 in a chronic plus binge therapeutic AH model will be critical to conduct clinical trials in AH patients. Once approved, SRT-015 is anticipated to greatly improve the lives of patients with severe AH.

每年美国约有500万人患急性酒精性肝炎 （AH），一种进行性炎症性肝损伤的综合征。在大多数AH患者中， 疾病是温和的。但是，对于严重急性AH的患者，早期死亡的风险很高，并且 对于最少的药理剂，需要进行密集管理。海豹 Rock Therapeutics正在开发SRT-015，这是一种有效和选择性的抑制剂 激活的Ask1激酶以满足这种未满足的需求。所有细胞中都存在ask1， 因应力因素（包括活性氧（ROS）， 细胞因子和LP。 SRT-015展示了直接抗炎，抗纤维化和 体外抗凋亡活性在刺激的人类免疫细胞，成纤维细胞和 肝细胞分别。 SRT-015治疗也被证明在体内有效 急性和慢性肝病小鼠模型，在GLP毒理学中证明了安全 研究。在第1阶段临床试验中，SRT-015的耐受性良好，无剂量限制 毒性。 SRT-015是包括AH在内的多种肝病的可能治疗方法。 在此SBIR R43中，我们将对SRT-015进行授权研究 严重的ah。这些研究旨在确定最小的有效性 暴露，定义临床相关的生物标志物，并表征 AH动物模型中SRT-015治疗后的微生物群和肠渗透性 目的1：估计SRT-015和效能生物标志物的最小有效暴露 慢性乙醇和暴饮暴食的AH动物模型。我们将使用鼠标 慢性lieber-decarli乙醇液体饮食（8周）以及最佳的暴饮暴食乙醇模型 反映人类AH病。最低有效剂量将使用三个 在慢性的最后四个星期内给予的SRT-015治疗剂量水平 评估了用于纤维化，炎症和肝毒性的乙醇进食和生物标志物。 目标2：评估肠道通透性，细菌易位和肠道 在治疗性AH动物模型中，SRT-015治疗后的营养不良。补充 并扩展功效数据，SRT-015对肠道的影响的全面表征 将进行炎症和肠道障碍功能。 证明SRT-015在慢性加狂饮治疗AH中的临床前功效 模型对于AH患者进行临床试验至关重要。一旦获得批准，SRT-015是 预计会大大改善严重AH患者的生活。