Development of the PTP1B inhibitor MSI-1436 for therapeutic stimulation of heart regeneration following acute myocardial infarction

开发 PTP1B 抑制剂 MSI-1436 用于刺激急性心肌梗塞后心脏再生的治疗

• 批准号: 9407383
• 负责人: Viravuth P Yin
• 金额: $ 76.97万
• 依托单位: REVIDIA THERAPEUTICS, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9407383
• 关键词: Acute; Acute myocardial infarction; Adult; Affect; Amputation; Animal Model; Animals; Applications Grants; Biodistribution; Biological Sciences; Blinded; Blood Vessels; Blood flow; Cardiac; Cardiac Function Study; Cardiac Myocytes; Cardiovascular system; Cause of Death; Cell Proliferation; Cessation of life; Cicatrix; Clinical; Clinical Trials; Collaborations; Coronary heart disease; Data Analyses; Development; Disease; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Drug vehicle; Echocardiography; Family suidae; Goals; Half-Life; Health Care Costs; Heart; Heart Diseases; Heart Injuries; Heart failure; Hemorrhage; Histology; Human; Hypertrophy; Individual; Infarction; Injury; Ischemia; Knowledge; Lead; Measures; Metabolism; Modeling; Morbidity - disease rate; Morphology; Mus; Myocardial Infarction; Myocardial Reperfusion; Myocardium; National Heart, Lung, and Blood Institute; Natural regeneration; Nerve; Non-Insulin-Dependent Diabetes Mellitus; Oxygen; PTPN1 gene; Patients; Pharmaceutical Preparations; Phase; Process; Protein Tyrosine Phosphatase; Protocols documentation; Randomized; Receptor Protein-Tyrosine Kinases; Recovery; Regenerative Medicine; Reperfusion Injury; Reperfusion Therapy; Research Personnel; Safety; Skeletal Muscle; Skin; Small Business Innovation Research Grant; Stem cells; System; Therapeutic; Time; Tissues; United States National Institutes of Health; Vascular blood supply; Work; World Health Organization; Zebrafish; bone; cardiac regeneration; clinically relevant; cost; drug testing; efficacy testing; experimental analysis; heart cell; heart function; improved; inhibitor/antagonist; injured; innovation; mortality; muscle regeneration; obesity treatment; pre-clinical; prevent; repaired; restoration; small molecule; stem; therapy development; tissue regeneration; tissue repair

PROJECT SUMMARY Heart disease is the leading cause of mortality and morbidity in the world. Coronary heart disease is the most common type of heart disease and results from the blockage of blood vessels that supply blood to the heart. A heart attack or myocardial infarction (MI) occurs when loss of blood flow causes the death of oxygen- starved cardiomyocytes. In humans, there is little or no significant cardiac muscle regeneration after an injury like a heart attack. Instead, dead cardiomyocytes are replaced by nonfunctional scar tissue, which weakens the heart and can lead ultimately to heart failure and death. Current therapies for heart attack are limited to reducing post-MI heart damage, preventing secondary heart attacks and treating resultant heart failure. Development of therapies that stimulate regeneration of the heart is a strategic priority for the National Heart Lung and Blood Institute. While under intensive study, no such therapies currently exist. MSI-1436 is potent and specific inhibitor of the tyrosine phosphatase PTP1B. PTP1B inactivates diverse receptor tyrosine kinases that regulate innate tissue repair and regeneration processes. Using blinded and randomized experimental and data analysis protocols, we have shown that MSI-1436 stimulates regeneration of adult zebrafish heart, connective, nerve, skin, bone and vascular tissues after amputation, and reverses genetically induced cardiac scar formation. In adult mice, MSI-1436 stimulates stem celI activation in injured skeletal muscle and increases survival, improves heart function ~2-fold, reduces infarct size by 53% and stimulates cellular proliferation 4.5-fold at 4 weeks post-MI. MSI-1436 was previously shown to be well tolerated by patients in Phase 1 and 1b clinical trials as a potential treatment for obesity and type-2 diabetes. The effects of MSI-1436 on regeneration occur at concentrations 50-fold lower than the maximum well tolerated human dose. The demonstrated safety of MSI-1436 and extensive knowledge of its target greatly reduce the time and costs associated with developing this drug as a regenerative medicine therapy for treating acute MI. We will test the efficacy of MSI-1436 in the restoration of heart function in a clinically relevant pig ischemia/reperfusion MI model. Porcine models have become the standard large animal system for studies of cardiac function due to similarities in heart morphology and metabolism to humans. Cardiac function will be measured by echocardiography and infarct size, cardiomyocyte regeneration and cardiomyocyte hypertrophy will be assessed by histology. Testing the efficacy of MSI-1436 in the pig is the required next step towards potential clinical trials. As with all our previous work, proposed pig studies will be blinded and randomized and will be performed in collaboration with lead investigators of the NIH/NHLBI sponsored Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR). Demonstrated efficacy in the pig will form an essential component of an FDA IND application for MSI-1436 clinical trials in MI patients.

项目概要 心脏病是世界上死亡和发病的主要原因。冠心病是 最常见的心脏病类型，是由向心脏供血的血管阻塞引起的 心。当血流减少导致氧气死亡时，就会发生心脏病或心肌梗塞（MI）。 饥饿的心肌细胞。在人类中，受伤后很少或没有显着的心肌再生 就像心脏病发作一样。相反，死亡的心肌细胞被无功能的疤痕组织取代，从而削弱了心肌细胞的功能。 心脏，最终可能导致心力衰竭和死亡。目前治疗心脏病的疗法仅限于 减少心肌梗死后心脏损伤，预防继发性心脏病发作并治疗由此导致的心力衰竭。 开发刺激心脏再生的疗法是国家的战略重点 心肺和血液研究所。虽然正在深入研究，但目前尚不存在此类疗法。 MSI-1436 是酪氨酸磷酸酶 PTP1B 的有效且特异性抑制剂。 PTP1B 失活 调节先天组织修复和再生过程的多种受体酪氨酸激酶。使用盲法 和随机实验和数据分析协议，我们已经证明 MSI-1436 刺激 成年斑马鱼截肢后心脏、结缔组织、神经、皮肤、骨骼和血管组织的再生，以及 逆转遗传引起的心脏疤痕形成。在成年小鼠中，MSI-1436 刺激干细胞活化 减少骨骼肌损伤并提高生存率，将心脏功能提高约 2 倍，将梗塞面积减少 53% 并在 MI 后 4 周刺激细胞增殖 4.5 倍。 MSI-1436 之前被证明效果良好 作为肥胖和 2 型糖尿病的潜在治疗方法，1 期和 1b 期临床试验中的患者能够耐受。 MSI-1436 对再生的影响发生在比最大孔浓度低 50 倍的浓度下 人体耐受剂量。 MSI-1436 已证明的安全性及其目标的广泛知识大大减少了 开发这种药物作为再生医学疗法用于治疗相关的时间和成本 急性心肌梗死。我们将测试 MSI-1436 在临床相关猪中恢复心脏功能的功效 缺血/再灌注心肌梗死模型。猪模型已成为研究以下疾病的标准大型动物系统 由于心脏形态和新陈代谢与人类相似，因此具有心脏功能。心脏功能将会 通过超声心动图测量梗塞面积、心肌细胞再生和心肌细胞肥大 将通过组织学评估。下一步需要测试 MSI-1436 在猪身上的功效 潜在的临床试验。与我们之前的所有工作一样，拟议的猪研究将是盲法和随机的，并且 将与 NIH/NHLBI 赞助联盟的主要研究人员合作进行 心脏保护治疗的临床前评估（CAESAR）。在猪身上表现出的功效 这是针对 MI 患者的 MSI-1436 临床试验 FDA IND 申请的重要组成部分。