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病之一与饮食相关的肝脂质积累（脂肪变性）相关，是常见的肝表现。包括糖尿病在内的肥胖和代谢综合征。调节疗法正在开发一种稳固的辅酶A脱发酶-1（SCD1）抑制剂用于治疗NAFLD和NASH。新型铅分子称为MTI-301是口服的生物利用且耐受性良好。带有MTI-301的小鼠的飞行员数据高脂肪饮食减弱了肝脏脂肪变性，并显着改善了肝功能。我们将利用数据在西方高脂饮食以及蛋氨酸 - 胆碱缺陷型（MCD）的临床前模型中产生饮食以测试MTI-301作为抗史塔斯顿单药治疗方案的功效。在此提案中，我们将测试我们用临床铅分子持续抑制SCD1的中心假设，MTI-301作为A 单个药物将减弱肝脂肪生成，减少甘油三酸酯的积累，并减少肝损伤，在饮食引起的NAFLD/NASH的啮齿动物模型中。为了在特定目标中检验我们的假设1 将利用NAFDL和NASH的公认的鼠模型，并用不同剂量的MTI-301在具体目的2，我们将评估MTI-301与抗糖尿病药物的Pioglitazone的组合疗法。由于肥胖和代谢综合征有助于肝脏脂肪变性的发展，我们预计结合可显着减少肝功能障碍。肝脂肪变性的预防或逆转是可以防止多种次级代谢疾病的重大治疗目标，从而增加发病率和全球死亡率。