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.

美国每年约有 500 万人患上急性酒精性肝炎 (AH)，一种进行性炎症性肝损伤综合征。在大多数 AH 患者中， 病情较轻。然而，严重急性 AH 患者早期死亡的风险较高，且 需要用最少的药物进行强化管理。海豹 Rock Therapeutics 正在开发 SRT-015，这是一种有效的选择性抑制剂 激活 ASK1 激酶来解决这一未满足的需求。 ASK1 存在于所有细胞中并且 响应包括活性氧 (ROS) 在内的应激因素而被激活， 细胞因子和脂多糖。 SRT-015 具有直接抗炎、抗纤维化和抗氧化作用 体外对受刺激的人体免疫细胞、成纤维细胞和成纤维细胞具有抗凋亡活性 分别为肝细胞。 SRT-015 治疗也被证明在体内有效 急性和慢性肝病小鼠模型并在 GLP 毒理学中证明是安全的 研究。在 1 期临床试验中，SRT-015 耐受性良好，无剂量限制 毒性。 SRT-015 可能是治疗包括 AH 在内的多种肝脏疾病的药物。 在此 SBIR R43 中，我们将开展 SRT-015 治疗的 IND 功效研究 严重的AH。这些研究旨在确定最低有效剂量 暴露，定义临床相关的生物标志物，并表征变化 AH 动物模型中 SRT-015 治疗后的微生物群和肠道通透性 目标 1：估计 SRT-015 的最低有效暴露量和功效生物标志物 慢性乙醇加暴食治疗性 AH 动物模型。我们将使用鼠标 慢性 Lieber-DeCarli 乙醇流质饮食（8 周）加狂饮乙醇模型效果最好 反映了人类AH疾病。最小有效剂量将使用三个确定 慢性病最后 4 周内 SRT-015 治疗的剂量水平 乙醇喂养和纤维化、炎症和肝毒性生物标志物的评估。 目标2：评估肠道通透性、细菌移位和肠道 在治疗性 AH 动物模型中，SRT-015 治疗后出现菌群失调。来补充 并扩展功效数据，全面表征 SRT-015 对肠道的影响 将进行炎症和肠道屏障功能检查。 展示 SRT-015 在慢性加暴食治疗性 AH 中的临床前疗效 模型对于在 AH 患者中进行临床试验至关重要。一旦获得批准，SRT-015 预计将大大改善严重 AH 患者的生活。