MTI-301 a SCD1 inhibitor for the treatment of NASH

MTI-301 一种 SCD1 抑制剂，用于治疗 NASH

基本信息

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
项目类别：
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

项目摘要

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.

抽象的：非酒精性脂肪肝病（NAFLD）是儿童和成人最常见的肝脏疾病之一与饮食相关的肝脏脂质堆积（脂肪变性）有关，是常见的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 (SCD1) 抑制剂，用于治疗 NAFLD 和 NASH。新型先导分子称为 MTI-301，具有口服生物利用度且耐受性良好。 MTI-301 在喂食西方蛋白质的小鼠中的试验数据高脂肪饮食减轻了肝脏脂肪变性并显着改善了肝功能。我们将利用数据在西方高脂肪饮食和蛋氨酸胆碱缺乏症 (MCD) 的临床前模型中产生饮食来测试 MTI-301 作为抗脂肪变性单药治疗选择的功效。在这个提案中我们将测试我们的中心假设是，临床先导分子 MTI-301 作为一种药物可持续抑制 SCD1 单药，会减弱肝脏脂肪生成，减少甘油三酯积累，并减少饮食诱导的 NAFLD/NASH 啮齿动物模型中的肝损伤。为了检验我们在特定目标 1 中的假设，我们将利用完善的 NAFDL 和 NASH 小鼠模型，并用不同剂量的 MTI-301 进行治疗具体目标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会导致肝脏脂肪变性的发生，我们预计联合用药可显着减轻肝功能障碍。预防或逆转肝脏脂肪变性是重要的治疗目标可以预防多种继发性代谢紊乱，从而增加发病率和全球死亡率。