TLC-1235, a controlled-release mitochondrial protonophore (CRMP), for the reversal of insulin resistance in patients with severe lipodystrophy

TLC-1235，一种控释线粒体质子载体 (CRMP)，用于逆转严重脂肪营养不良患者的胰岛素抵抗

• 批准号: 10600727
• 负责人: Rob Myers
• 金额: $ 30万
• 依托单位: ORSOBIO, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10600727
• 关键词: 2,4-Dinitrophenol; Achievement; Address; Adenosine Triphosphate; Adverse effects; Animal Disease Models; Animals; Biological; Body Weight decreased; Canis familiaris; Cell membrane; Clinical Research; Data; Diabetes Mellitus; Diglycerides; Dinitrophenols; Disease; Dose; Drug Interactions; Drug Kinetics; Dyslipidemias; Electron Transport; Energy Metabolism; Exhibits; Familial generalized lipodystrophy; Fatty Liver; Formulation; Funding; Hepatic; Homeostasis; Hyperthermia; Hypertriglyceridemia; Injury; Inner mitochondrial membrane; Insulin Receptor; Insulin Resistance; Investigational Drugs; Investigational New Drug Application; Lead; Leptin; Leptin deficiency; Link; Lipids; Lipodystrophy; Liver; Medical; Membrane Lipids; Metabolic; Mitochondria; Modeling; Muscle; No-Observed-Adverse-Effect Level; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Oral; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase; Pre-Clinical Model; Preparation; Production; Protein Kinase; Protons; Rattus; Reactive Oxygen Species; Receptor Signaling; Rights; Risk; Safety; Therapeutic; Therapeutic Index; Time; Toxicology; Treatment Efficacy; Triglycerides; United States Food and Drug Administration; Universities; Work; base; controlled release; drug metabolism; effective therapy; fatty acid oxidation; first-in-human; good laboratory practice; human study; inflammatory marker; insulin sensitivity; nonalcoholic steatohepatitis; novel strategies; oxidation; programs; small molecule; systemic toxicity

TLC-1235, a controlled-release mitochondrial protonophore (CRMP), for the reversal of insulin resistance in patients with severe lipodystrophy Abstract Patients with lipodystrophies exhibit hypertriglyceridemia, severe insulin resistance, type 2 diabetes mellitus, and nonalcoholic steatohepatitis (NASH), and have limited effective treatment options. Lipodystrophy is characterized by the ectopic accumulation of lipids in liver and muscle. Increased lipids, specifically sn-1,2- diacylglycerol, within plasma membranes interfere with insulin receptor signaling and are a central mechanism for insulin resistance. Mitochondrial protonophores reduce intracellular lipids by increasing lipid oxidation in the mitochondria. Mechanistically, mitochondrial protonophores shuttle protons across the inner mitochondrial membrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncoupling nutrient oxidation from ATP production and dissipating the proton gradient as heat. The therapeutic efficacy of protonophores is linked to 1) increased oxidation of fatty acids to compensate for inefficient ATP production, 2) a decrease in the production of reactive oxygen species (ROS) from the electron transport chain, and 3) activation of the expression of AMP protein kinase (AMPK), the master regulator of cellular energy homeostasis. Thus, small molecule mitochondrial protonophores represent a novel strategy to reduce ectopic lipid accumulation by increasing cellular energy expenditure. Indeed, multiple groups have validated this mechanism of action by demonstrating large improvements in insulin sensitivity and dyslipidemia, with concomitant reductions in hepatic triglycerides and markers of inflammation in relevant nonclinical models. TLC-1235 is a functionally liver-targeted, controlled-release mitochondrial protonophore (CRMP) that will promote selective mitochondrial uncoupling in the liver while minimizing high systemic exposures (Cmax) that have been associated with adverse effects of systemic uncoupling including hyperthermia, excessive weight loss, and muscle injury. During this Direct-to-Phase-2 project, we will initiate Investigational New Drug (IND)-enabling activities for TLC- 1235, including Good Laboratory Practice (GLP) manufacturing, drug metabolism and pharmacokinetics (DMPK), and toxicology and safety pharmacology studies. Additional work to support the filing of an IND will be funded by the Company.

TLC-1235，一种可控制释放的线粒体原载体(CRMP)，用于逆转胰岛素 严重脂营养不良患者的抵抗力 摘要 脂营养不良的患者表现为高甘油三酯血症，严重的胰岛素抵抗，2型糖尿病， 和非酒精性脂肪性肝炎(NASH)，有效的治疗选择有限。脂肪营养不良是 以肝脏和肌肉中脂肪的异位堆积为特征。血脂升高，特别是sn-1，2- 质膜中的二酰甘油干扰胰岛素受体信号转导，是一种中心机制 治疗胰岛素抵抗。线粒体原载体通过增加细胞内脂质氧化降低细胞内脂质 线粒体。从机制上讲，线粒体原生质体能将质子穿梭于线粒体内部 膜通过不依赖于三磷酸腺苷(ATP)合成酶的途径，从而解偶联 从三磷酸腺苷生产的养分氧化和消散作为热量的质子梯度。丹参的临床疗效观察 原生物体与1)脂肪酸的氧化增加以补偿低效的ATP产生有关，2) 电子传递链中产生的活性氧物种(ROS)减少，以及3) 激活AMP蛋白激酶(AMPK)的表达，AMPK是细胞能量稳态的主要调节因子。 因此，小分子线粒体原载体代表了一种降低异位脂质的新策略 通过增加细胞能量消耗来积累。事实上，多个小组已经验证了这一机制 通过显示胰岛素敏感性和血脂异常的大幅改善以及伴随而来的行动 相关非临床模型中肝脏甘油三酯和炎症标志物的减少。TLC-1235是一种 功能性肝靶向、控制释放的线粒体原载体(CRMP)将促进选择性 肝脏线粒体解偶联，同时最大限度地减少相关的高系统性暴露(Cmax) 全身脱钩的不良反应包括体温过高、体重过度减轻和肌肉损伤。 在这个直接到第二阶段的项目中，我们将启动TLC的研究性新药(IND)支持活动- 1235，包括良好实验室规范(GLP)的制造、药物代谢和药代动力学 (DMPK)，以及毒理学和安全药理学研究。支持IND备案的其他工作将是 由本公司提供资金。