MTI-301 a SCD1 inhibitor for the treatment of NASH

摘要： 非酒精性脂肪肝(NAFLD)是儿童和成人最常见的肝病之一 与饮食相关的肝脏脂肪堆积(脂肪变性)有关，是一种常见的 肥胖和包括糖尿病在内的代谢综合征。调制治疗公司正在开发一种硬脂酰基- 辅酶A去饱和酶-1(SCD1)抑制剂用于治疗NAFLD和NASH。一种新型的铅分子 被称为MTI-301的口服生物利用度和耐受性良好。MTI-301在喂食西药的小鼠中的试验数据 高脂饮食可减轻肝脏脂肪变性，明显改善肝功能。我们将利用数据 在西方高脂饮食和蛋氨酸胆碱缺乏症(MCD)的临床前模型中产生 饮食检测MTI-301作为抗脂肪变性单药治疗方案的疗效。在本提案中，我们将测试 我们的中心假设是通过临床先导分子MTI-301持续抑制SCD1 单一药物，将减弱肝脏脂肪生成，减少甘油三酯积聚，以及减少 饮食诱导的NAFLD/NASH啮齿动物模型的肝损伤。为了在特定目标1中测试我们的假设，我们 将利用已建立的NAFDL和NASH小鼠模型并用不同剂量的MTI-301治疗 具体目的2，我们将评估MTI-301与降糖药物吡格列酮的联合治疗。 由于肥胖和代谢综合征有助于肝脏脂肪变性的发展，我们预计 联合用药能明显减轻肝功能障碍。预防或逆转肝脏脂肪变性是一种 重要的治疗目标，可以预防增加发病率的多种继发性代谢紊乱 以及全球范围内的死亡率。

Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in children and adults associated with diet-associated hepatic lipid accumulation (steatosis), and is a common hepatic manifestation of obesity and metabolic syndromes including diabetes. Modulation Therapeutics is developing a stearoyl- coenzyme A desaturase-1 (SCD1) inhibitor for the treatment of NAFLD and NASH. The novel lead molecule referred to as MTI-301 is orally bioavailable and well-tolerated. Pilot data with MTI-301 in mice fed a Western high fat diet attenuated the liver steatosis and significantly improved liver function. We will leverage data generated in pre-clinical models of both a Western high fat diet as well as a Methionine-choline-deficient (MCD) diet to test the efficacy of MTI-301 as anti-steatosis single agent treatment option. In this proposal we will test our central hypothesis that sustained inhibition of SCD1 with the clinical lead molecule, MTI-301 as a single agent, will attenuate hepatic lipogenesis, reduce triglyceride accumulation, as well as reduce the liver injury, in diet-induced rodent models of NAFLD/NASH. To test our hypothesis in specific aim 1 we will utilize a well-established murine model of NAFDL and NASH and treat with different doses of MTI-301 In specific aim 2, we will evaluate the combination therapy of MTI-301 with pioglitazone, an anti-diabetic drug. Since obesity and metabolic syndromes contribute to the development of liver steatosis, we expect the combination to be reduce the liver dysfunction significantly. Prevention or reversal of liver steatosis is a significant therapeutic goal which can prevent multiple secondary metabolic disorders which increases morbidity and mortality worldwide.