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

项目摘要 心脏病是世界上死亡和发病的主要原因。冠心病是 心脏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。 心心脏病发作或心肌梗死（MI）发生时，血流损失导致氧气死亡- 饥饿的心肌细胞在人类中，受伤后很少或没有明显的心肌再生 比如心脏病发作相反，死亡的心肌细胞被无功能的疤痕组织所取代， 最终可能导致心力衰竭和死亡。目前治疗心脏病发作的方法仅限于 减少MI后心脏损伤，预防继发性心脏病发作和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。虽然正在进行深入研究，但目前还不存在此类疗法。 MSI-1436是酪氨酸磷酸酶PTP1B的有效和特异性抑制剂。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。使用设盲 和随机实验和数据分析协议，我们已经表明，MSI-1436刺激， 截肢后成年斑马鱼心脏、结缔组织、神经、皮肤、骨和血管组织的再生，以及 逆转基因诱导的心脏瘢痕形成。在成年小鼠中，MSI-1436刺激干细胞活化， 损伤骨骼肌，提高存活率，改善心脏功能~2倍，减少梗死面积53% 并在MI后4周刺激细胞增殖4.5倍。MSI-1436以前被证明是很好的 在1期和1b期临床试验中被患者耐受，作为肥胖和2型糖尿病的潜在治疗方法。 MSI-1436对再生的影响发生在比最大孔低50倍的浓度下。 人体耐受剂量 MSI-1436的已证实安全性及其靶点的广泛知识大大降低了 与开发这种药物作为再生医学治疗相关的时间和成本 急性心肌梗死我们将测试MSI-1436在临床相关猪的心脏功能恢复中的功效 缺血/再灌注MI模型。猪模型已成为研究的标准大型动物系统， 由于心脏形态和代谢与人类相似，因此心脏功能。心脏功能将 通过超声心动图和梗死面积、心肌细胞再生和心肌细胞肥大测量 将通过组织学进行评估。测试MSI-1436在猪中的有效性是下一步的必要步骤， 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化的， 将与NIH/NHLBI赞助的联盟的主要研究者合作进行， 心脏保护治疗的临床前评估（CAESAR）。在猪中证实的有效性将形成 MI患者MSI-1436临床试验的FDA IND申请的重要组成部分。

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.