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-1235，一种受控的线粒体质子团（CRMP），用于胰岛素的逆转 严重脂肪营养不良患者的抗药性 抽象的 脂肪营养不良的患者表现出高甘油三酯血症，严重的胰岛素抵抗，2型糖尿病，Mellitus， 和非酒精性脂肪性肝炎（NASH），并且有效的治疗选择有限。脂肪营养不良 以脂质在肝脏和肌肉中的异位积累为特征。脂质增加，特别是SN-1,2- 二酰基甘油，在质膜内部干扰胰岛素受体信号，是一种中心机制 用于胰岛素抵抗。线粒体质子团通过增加脂质氧化而减少细胞内脂质 线粒体。从机械上讲，线粒体质子团穿过内部线粒体的质子 膜通过独立于三磷酸腺苷（ATP）合酶的途径，从而解开 ATP产生的营养氧化并将质子梯度耗散为热量。的治疗功效 质子团与1）脂肪酸的氧化增加有关，以补偿效率低下的ATP产生，2） 电子传输链中活性氧（ROS）的产生减少，3） 细胞能量稳态的主要调节剂AMP蛋白激酶（AMPK）的表达激活。 因此，小分子线粒体质子团代表了减少异位脂质的新型策略 通过增加细胞能量消耗来积累。确实，多个小组已经验证了这种机制 通过证明胰岛素敏感性和血脂异常的大量改善，具有作用 相关非临床模型中肝甘油三酸酯和炎症标记的减少。 TLC-1235是a 功能上肝靶向，控制释放线粒体质子团（CRMP），将促进选择性 肝脏中的线粒体解偶联，同时最大程度地减少已关联的高全身性暴露（CMAX） 全身解偶联的不良影响，包括高温，体重减轻过多和肌肉损伤。 在这个直接到相关的项目中，我们将启动研究新药（IND）的TLC-的活动 1235年，包括良好的实验室实践（GLP）制造，药物代谢和药代动力学 （DMPK）和毒理学和安全药理学研究。支持提交IND的其他工作将是 由公司资助。