Evaluating the efficacy of a novel NASH therapeutic

评估新型 NASH 疗法的疗效

基本信息

批准号：
10698971
负责人：
Alison Nicole McCracken
金额：
$ 29.82万
依托单位：
SIEGE PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10698971
关键词：
Address Adult Affect Agonist American Anti-Inflammatory Agents Biochemical Biological Availability Biological Models Body Weight decreased Brain Cells Characteristics Cirrhosis Crowding Defect Development Diet Disease Disease Progression Disease model Dissection FDA approved Fatty Liver Fatty acid glycerol esters Female Fibrosis Functional disorder Funding Future Generations Goals Health Hepatic Hepatocyte High Fat Diet Histology Human Individual Inflammation Left Liver Liver Dysfunction Measures Metabolic Metabolic dysfunction Metabolic syndrome Mitochondria Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Normal tissue morphology Obesity Oral Pathologic Pathology Patients Performance Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Positioning Attribute Prevalence Primary carcinoma of the liver cells Publishing Reactive Oxygen Species Risk Severity of illness Stimulus Testing Therapeutic Tissue Model Tissues Toxic effect Triglycerides United States Validation Work aged cardiovascular disorder risk cell type chronic liver disease clinically relevant comorbidity comparison control cytokine diet-induced obesity efficacy evaluation endoplasmic reticulum stress glucagon-like peptide 1 glucose metabolism human model improved islet amyloid polypeptide male molecular marker mouse model non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel strategies phase III trial predictive modeling prevent programs protective effect small molecule success

项目摘要

PROJECT SUMMARY Obesity and other characteristics of metabolic syndrome are key underlying factors in the development of non- alcoholic fatty liver disease (NAFLD). If left unchecked, NAFLD can progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. Up to 60% of the 80-100 million Americans with NAFLD will progress to NASH, yet there are no FDA-approved therapeutics; the only treatment option currently available is weight loss. The overall objective of this project is to determine whether the Siege compound merits development as a NASH therapy. Recently published work demonstrates improvement of liver phenotypes in a diet-induced obesity model without toxicity in normal tissues and thus the potential to address an as-yet unmet need for NASH patients. Siege Pharmaceuticals is taking a new approach to treating this disease: correcting ROS, ER stress, and hyperleptinemia upstream of liver dysfunction, inflammation, and fibrosis instead of just targeting the pheno- types without addressing the root cause. Aim 1 will evaluate the efficacy of Siege’s compound in a mouse model that reproduces the pathological features seen in patients with NASH while Aim 2 will test SGE-893 in a liver microtissue model derived from primary human cells, allowing for dissection of liver-specific and weight loss- driven effects and validation in a human model system. These studies will establish whether development as a NASH therapeutic is merited and could support a future Phase II program. If the Siege compound performs as expected, both improving NASH phenotypes and correcting metabolic dysfunction, it could dramatically im- prove the overall health of patients who currently have no therapeutic options.

项目摘要肥胖和代谢综合征的其他特征是非 - 酒精脂肪肝病（NAFLD）。如果不受限制地检查，NAFLD可以发展为非酒精性脂肪性肝炎（NASH），肝硬化和肝细胞癌。在拥有NAFLD的80-1亿美国人中，多达60％将纳什（Nash）的进展，但没有FDA批准的疗法。当前可用的唯一治疗选择是减肥。该项目的总体目标是确定攻城化合物是否值得开发作为纳什疗法。最近发表的工作表明饮食引起的肝脏表型的改善肥胖模型在正常时机中没有毒性，因此有可能解决纳什尚未满足的需求患者。攻城药正在采用一种新方法来治疗这种疾病：纠正ROS，ER应力，以及肝功能障碍，注射和纤维化上游的高血治血症，而不仅仅是针对现象类型没有解决根本原因。 AIM 1将评估鼠标模型中攻城化合物的效率这重现了NASH患者中看到的病理特征，而AIM 2将在肝脏中测试SGE-893 源自原代人类细胞的微动物模型，可以解剖肝脏特异性和体重减轻 - 人类模型系统中的驱动效果和验证。这些研究将确定发展是否 NASH治疗是值得的，可以支持未来的II期计划。如果攻城化合物的表现为预期的是，既改善NASH表型和纠正代谢功能障碍，都可能非常明显证明目前没有治疗选择的患者的整体健康状况。