MTI-301 a SCD1 inhibitor for the treatment of NASH

MTI-301 一种 SCD1 抑制剂，用于治疗 NASH

• 批准号: 10693638
• 负责人: Werner Geldenhuys
• 金额: $ 34.49万
• 依托单位: MODULATION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10693638
• 关键词: Adult; Affect; Agonist; Antidiabetic Drugs; Appearance; Attenuated; Benchmarking; Biological Availability; Biological Markers; Blood; Canis familiaris; Cause of Death; Child; Chronic Disease; Clinical; Clinical Management; Coenzyme A; Combined Modality Therapy; DNA Sequence Alteration; Data; Diabetes Mellitus; Diet; Disease; Dose; Drug Kinetics; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzymes; Epidemic; FDA approved; Fatty Liver; Goals; Hepatic; Hepatocyte; High Fat Diet; Human; In Vitro; Incidence; Inpatients; Lead; Legal patent; Lipids; Liver; Liver Dysfunction; Liver Failure; Liver Fibrosis; Liver Function Tests; Liver Microsomes; Liver diseases; Measures; Medicine; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Methionine; Mitochondria; Modeling; Monounsaturated Fatty Acids; Morbidity - disease rate; Mus; Nonesterified Fatty Acids; Obesity; Oleates; Oral; Outpatients; Patient Care; Patient-Focused Outcomes; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phosphotransferases; Pioglitazone; Plasma; Play; Population; Pre-Clinical Model; Prevention; Progressive Disease; Rattus; Reaction; Reducing diet; Rodent Model; Syndrome; Testing; Therapeutic; Toxicokinetics; Triglycerides; Type 2 diabetic; attenuation; choline deficient diet; clinical development; comorbidity; desaturase; efficacy testing; enzyme activity; fatty acid oxidation; gene repression; improved; in vivo; inhibitor; insulin sensitivity; lipid biosynthesis; liver development; liver function; liver injury; mortality; mouse model; new therapeutic target; non-alcoholic fatty liver; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; palmitoleic acid; pharmacologic; prevent; socioeconomics; stearoyl-coenzyme A; treatment strategy; validation studies; western diet

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.

摘要： 非酒精性脂肪性肝病（NAFLD）是儿童和成人最常见的肝病之一 与饮食相关的肝脏脂质蓄积（脂肪变性）相关，是肝硬化的常见肝脏表现。 肥胖和代谢综合征包括糖尿病。Modulation Therapeutics正在开发一种硬脂酰- 辅酶A去饱和酶-1（SCD 1）抑制剂，用于治疗NAFLD和NASH。新型铅分子 被称为MTI-301的化合物是口服生物可利用的并且耐受性良好。MTI-301在喂食Western blot的小鼠中的初步数据 高脂饮食减轻了肝脏脂肪变性，并显著改善了肝功能。我们将利用数据 在西方高脂肪饮食和蛋氨酸胆碱缺乏（MCD）的临床前模型中产生 饮食以测试MTI-301作为抗脂肪变性单一药剂治疗选择的功效。在本提案中，我们将测试 我们的中心假设是，用临床先导分子MTI-301持续抑制SCD 1， 单药，将减弱肝脂肪生成，减少甘油三酯积累，以及减少 肝脏损伤，在饮食诱导的NAFLD/NASH啮齿动物模型中。为了检验我们在具体目标1中的假设，我们 将利用完善的NAFDL和NASH鼠模型并用不同剂量的MTI-301治疗， 具体目标2，我们将评估MTI-301与抗糖尿病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 联合用药可明显减轻肝功能损害。预防或逆转肝脏脂肪变性是一种 可预防增加发病率的多种继发性代谢紊乱的重要治疗目标 和死亡率。