Evaluating the efficacy of a novel NASH therapeutic

项目摘要 肥胖和代谢综合征的其他特征是非代谢综合征发生的关键潜在因素。 酒精性脂肪肝（NAFLD）。如果不加以控制，NAFLD可进展为非酒精性脂肪性肝炎 （NASH）、肝硬化和肝细胞癌。高达60%的80-100万美国人与NAFLD将 进展为NASH，但没有FDA批准的治疗方法;目前唯一可用的治疗选择是 减肥.该项目的总体目标是确定围攻大院是否值得开发 作为NASH治疗。最近发表的工作表明，改善肝脏表型的饮食诱导 在正常组织中没有毒性的肥胖模型，因此有可能解决尚未满足的NASH需求 患者Siege制药公司正在采取一种新的方法来治疗这种疾病：纠正ROS，ER应激， 和高瘦素血症上游的肝功能障碍，炎症和纤维化，而不仅仅是针对表型， 没有解决根本原因。目的1将评估Siege化合物在小鼠模型中的功效 Aim 2将在肝脏中测试SGE-893， 源自原代人类细胞的微组织模型，允许解剖肝脏特异性和体重减轻- 在人体模型系统中的驱动效果和验证。这些研究将确定发展是否是一种 NASH治疗是值得的，可以支持未来的II期计划。如果围城区的表现 预期，无论是改善NASH表型和纠正代谢功能障碍，它可以显着改善- 证明目前没有治疗选择的患者的整体健康状况。

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.