Remogliflozin Etabonate Effect on Primary Biliary Cholangitis

项目摘要 原发性胆汁性胆管炎（PBC）是一种严重的慢性胆汁淤积性肝病， 进行性的、以自身免疫为基础的胆管破坏，以及肝硬化的最终发作及其 并发症FDA批准用于PBC管理的药物有限，但在许多情况下， 需要进行肝移植，这是完全治愈的唯一机会。因此，有效 迫切需要治疗PBC和延迟肝移植的时间以及改善 PBC患者的生活质量。考虑到这一目标，治疗PBC的新方法是 如下所述这些发展是基于观察到，remoglitazone etabonate， SGLT 2抑制剂与其他SGLT 2抑制剂具有独特的差异化特性，可防止 在肝损伤的鼠模型中PBC疾病病理学的进展。基于我们令人信服的 根据初步数据，本概念验证研究的I期确认将证明， 依碳酸再格列净是一种潜在的PBC治疗药物。我们将通过以下方式实现这些目标 目的：1）评价再胶质化酶和其他SGLT抑制剂在体外肝细胞中的作用。SGLTs 在胆管中表达，抑制SGLT会导致胆汁流量增加; 2）证实 我们早期观察到依碳酸去格列汀可以预防或逆转PBC进展， 一种广为接受的PBC小鼠模型。

Project Summary Primary biliary cholangitis (PBC) is a serious, chronic cholestatic liver disease characterized by a progressive, autoimmune-based destruction of the bile duct, and the eventual onset of cirrhosis and its complications. There are limited FDA-approved drugs for the management of PBC, but in many cases liver transplantation is required and offers the only chance for a complete cure. Therefore, effective treatments are urgently needed to treat PBC and to delay time to liver transplantation and to improve the quality of life for PBC patients. With that goal in mind, a novel approach for treating PBC is described below. These developments are based on the observation that remogliflozin etabonate, an SGLT2 inhibitor with unique differentiating properties from other SGLT2 inhibitors, prevents the progression of PBC disease pathology in a murine model of liver damage. Based on our compelling preliminary data, this Phase I confirmation of proof-of-concept study will demonstrate that remogliflozin etabonate is a potential therapy for PBC. We will achieve these goals by the following Aims: 1) Evaluate the role of remogliflozin and other SGLT inhibitors in liver cells in vitro. SGLTs are expressed in biliary ducts and inhibition of SGLTs causes increased biliary flow; and 2) Confirm in vivo our earlier observation that remogliflozin etabonate can prevent or reverse PBC progression using a well-accepted murine model of PBC.