Development of Controlled Release Mitochondrial Protonophore (CRMP) as a Novel Treatment for Type-2 Diabetes and Non-Alcoholic Steatohepatitis in Dysmetabolic Non-Human Primates

开发控释线粒体原细胞 (CRMP) 作为代谢失调的非人类灵长类动物 2 型糖尿病和非酒精性脂肪性肝炎的新型治疗方法

• 批准号: 10352445
• 负责人: GERALD I SHULMAN
• 金额: $ 53.21万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10352445
• 关键词: Acetyl Coenzyme A; Adipocytes; Affect; Behavior; Body Composition; Body Weight; Body Weight decreased; Caloric Restriction; Cell secretion; Chronic; Closure by clamp; Data; Development; Diacylglycerol Kinase; Diglycerides; Disease Resistance; Eating; Fatty Liver; Fatty acid glycerol esters; General Population; Generations; Gluconeogenesis; Glucose; Glucose Clamp; Glycerol; Grant; Hepatic; Human; Hyperinsulinism; Hypertriglyceridemia; Induced Hyperthermia; Insulin; Insulin Resistance; Lipids; Liquid Chromatography; Liver; Liver Fibrosis; Liver Mitochondria; Macaca mulatta; Measurement; Measures; Mediating; Metabolic; Metabolic syndrome; Methodology; Methods; Mitochondria; Modeling; Monitor; Monkeys; Muscle; NMR Spectroscopy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Palmitates; Pathogenesis; Placebos; Plasma; Predisposing Factor; Pyruvate Carboxylase; Pyruvate Kinase; Research; Rodent; Rodent Model; Safety; Steatohepatitis; Structure of beta Cell of islet; Syndrome; Therapeutic Agents; Therapeutic Index; Tissues; Tracer; Triglycerides; Uncoupling Agents; ceramide kinase; clinically relevant; cohort; controlled release; cytokine; design; efficacy evaluation; fatty acid oxidation; global health; glucose production; human model; improved; insulin sensitivity; intravenous glucose tolerance test; ketogenesis; liver biopsy; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; nonhuman primate; novel; novel drug class; novel therapeutic intervention; novel therapeutics; oxidation; protein activation; protein kinase C epsilon; pyruvate dehydrogenase; side effect; stable isotope; success; systemic toxicity; tandem mass spectrometry; treatment strategy

Non-alcoholic fatty liver disease (NAFLD) is estimated to occur in one third of the general population and is a major predisposing factor in the pathogenesis of hepatic insulin resistance and type 2 diabetes (T2D). NAFLD occurs when lipid supply to the liver exceeds rates of lipid oxidation and lipid export. A number of therapies have been employed to reduce ectopic-fat accumulation in liver and hepatic insulin resistance, however these approaches have been met with limited success in the long-term and new therapies are required. In order to meet this great unmet need, our lab has recently developed a Controlled Release Mitochondrial Protonophore (CRMP) that is functionally liver-targeted and causes increased mitochondrial fat oxidation by promoting a subtle sustained increase in hepatic mitochondrial uncoupling activity. Importantly, we have previously demonstrated that CRMP safely reverses hypertriglyceridemia, fatty liver, steatohepatitis and liver fibrosis in rodent models of NAFLD/NASH/liver fibrosis and T2D without inducing hyperthermia, weight loss or any associated hepatic/systemic toxicities. Taken together, these rodent studies provide important proof of concept for the further assessment of CRMP as a novel therapeutic strategy for the treatment of NAFLD/NASH and T2D in a highly relevant non-human primate model of NAFLD and the dysmetabolic syndrome. Therefore, in the present proposal, we aim to determine the safety and efficacy of chronic CRMP treatment on the reversal of hypertriglyceridemia, NAFLD, and liver and muscle insulin resistance in dysmetabolic, spontaneously obese Rhesus monkeys. In addition, we will perform a comprehensive set of hepatic metabolic flux measurements using state-of-the-art liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance spectroscopy methods to directly assess the impact of chronic CRMP treatment on rates of hepatic mitochondrial fatty acid oxidation, gluconeogenesis, pyruvate dehydrogenase flux, pyruvate kinase flux and hepatic ketogenesis in this obese dysmetabolic monkey model of NAFLD. We hypothesize that chronic CRMP treatment will reverse NAFLD and improve whole-body insulin responsiveness in obese dysmetabolic Rhesus monkeys in a safe and effective manner by promoting increased rates of hepatic mitochondrial fatty acid oxidation independent of changes in food intake/body weight. Collectively, the results of this research will be highly impactful in that they will provide important proof-of-concept and safety data in a highly relevant clinical model of obese dysmetabolic non-human primates to support the development of novel liver-targeted mitochondrial uncoupling agents for the treatment of NAFLD/NASH and T2D in humans.

据估计，三分之一的普通人群患有非酒精性脂肪性肝病 (NAFLD)，它是肝胰岛素抵抗和 2 型糖尿病 (T2D) 发病机制的主要诱发因素。当肝脏的脂质供应超过脂质氧化和脂质输出的速率时，就会发生 NAFLD。已采用多种疗法来减少肝脏中的异位脂肪积累和肝脏胰岛素抵抗，但从长远来看，这些方法取得的成功有限，需要新的疗法。为了满足这一巨大的未满足的需求，我们的实验室最近开发了一种控释线粒体原细胞（CRMP），它在功能上以肝脏为靶点，通过促进肝脏线粒体解偶联活性的微妙持续增加来增加线粒体脂肪氧化。重要的是，我们之前已经证明，CRMP 可以安全地逆转 NAFLD/NASH/肝纤维化和 T2D 啮齿动物模型中的高甘油三酯血症、脂肪肝、脂肪性肝炎和肝纤维化，而不引起高热、体重减轻或任何相关的肝脏/全身毒性。总而言之，这些啮齿动物研究为进一步评估 CRMP 作为一种在高度相关的非人类灵长类 NAFLD 和代谢障碍综合征模型中治疗 NAFLD/NASH 和 T2D 的新治疗策略提供了重要的概念证明。因此，在本提案中，我们的目标是确定慢性 CRMP 治疗对逆转代谢障碍、自发性肥胖恒河猴的高甘油三酯血症、NAFLD 以及肝脏和肌肉胰岛素抵抗的安全性和有效性。此外，我们将使用最先进的液相色谱-串联质谱和核磁共振波谱方法进行一套全面的肝脏代谢通量测量，以直接评估慢性 CRMP 治疗对肝线粒体脂肪酸速率的影响NAFLD 肥胖代谢异常猴模型中的氧化、糖异生、丙酮酸脱氢酶通量、丙酮酸激酶通量和肝酮生成。我们假设，慢性 CRMP 治疗将通过促进肝线粒体脂肪酸氧化速率的增加（与食物摄入量/体重的变化无关），以安全有效的方式逆转 NAFLD 并改善肥胖代谢障碍恒河猴的全身胰岛素反应性。总的来说，这项研究的结果将具有高度影响力，因为它们将在肥胖代谢异常非人类灵长类动物高度相关的临床模型中提供重要的概念验证和安全性数据，以支持新型肝脏靶向线粒体解偶联剂的开发用于治疗人类 NAFLD/NASH 和 T2D。