Committed Cardiac Progenitors to Remuscularize the Failing Ischemic Heart

项目总结/摘要 由于心肌细胞和细胞外基质的破坏而导致的收缩性心肌的丧失， 心肌梗死（MI）的标志。大面积MI或反复MI的后果是进行性的 左心室扩大慢性心力衰竭和死亡。心脏移植可以挽救生命;然而， 严重的整体器官短缺阻碍了这种疗法的广泛采用。因此，MI后心力衰竭持续 是一个重大的公共卫生挑战。基于细胞的治疗已经发展成为一种诱人的再生医学， 预防心肌梗死后重塑的方法;然而，使用骨髓、脂肪、骨骼肌 而成人心脏来源的细胞没有显示出或仅显示出适度的益处。电池保持力差，无法更换 心肌细胞和补充心脏细胞外基质是该领域的关键屏障。 我们提出了一种治疗方案，使用一种创新的人群， iPSC衍生的定向心脏祖细胞（CCP）与天然心脏成纤维细胞衍生的 细胞外基质（cECM），以改善细胞保留和恢复受损的基质。CCP有一个 它具有成为心肌细胞的非凡能力，这些心肌细胞整合在受损的心肌中。cECM结合至 治疗细胞，并改善其在心脏组织中的保留。此外，初步数据表明，cECM 通过免疫调节、血管生成和基质替代改善心肌的健康。 CCP和cECM都可以制造成窄规格和高规模。 我们假设肌内联合施用CCP与cECM将使肌肉化。 心肌和改善心脏功能更有效地比任何产品单独。为了验证这个假设， 我们将在临床上具有代表性的猪心肌梗死后慢性心脏中测量这种方法的有效性和安全性 失效模式首先，猪将经历冠状动脉球囊闭塞和再灌注MI，随后4周 随后通过微创、经血管内注射CCP + cECM、单独的CCP、单独的cECM或假手术。 收缩性、腔室几何形状、活力和应变分析将使用定量磁共振成像进行。 共振成像将进行详细的组织病理学检查。将植入连续ECG记录器 心律失常监测主要疗效终点为射血分数从基线至 3个月 威斯康星大学麦迪逊分校的高素质研究人员将与富士胶片细胞合作 动力公司，麦迪逊，威斯康星州（CCP制造商）和蜂窝物流公司，Sun Prairie，WI （cECM的制造商，也称为CellogicusTM），以确保仔细的科学严谨性适用于此 研究性新药（IND）启动项目。本研究的设计经过仔细考虑， 根据FDA/CBER指南，并将受益于通过再生 Medicine Innovation Catalyst加速治疗产品开发并为未来的人体试验提供信息。

PROJECT SUMMARY / ABSTRACT The loss of contractile myocardium resulting from the destruction of cardiac cells and extracellular matrix is the hallmark of myocardial infarction (MI). The consequence of a large MI or repeated MI’s is progressive enlargement of the left ventricle, chronic heart failure and death. Heart transplant can save lives; however, critical whole organ shortages prevent wide adoption of this therapy. Therefore, post MI heart failure continues to be a major public health challenge. Cell-based therapy has evolved as a tantalizing, regenerative medicine, approach to prevent post-MI remodeling; however, clinical trials using bone marrow, adipose, skeletal muscle and adult cardiac-derived cells have shown no or only modest benefit. Poor cell retention, failure to replace cardiomyocytes and to replenish cardiac extracellular matrix are critical barriers in the field. We propose a therapeutic solution to remuscularize the myocardium using an innovative population of human iPSC-derived committed cardiac progenitors (CCPs) in combination with a natural cardiac fibroblast-derived extracellular matrix (cECM) to improve cell retention and restore damaged matrix. CCPs have an extraordinary ability to become cardiomyocytes that integrate in damaged myocardium. cECM binds to therapeutic cells and improves their retention in cardiac tissue. In addition, preliminary data suggests cECM improves the health of the myocardium through immunomodulation, angiogenesis and matrix replacement. Both CCPs and cECM can be manufactured to narrow specifications and high scale. We hypothesize that intramuscular co-administration of CCP combined with cECM will remuscularize the myocardium and improve cardiac function more effectively than either product alone. To test this hypothesis, we will measure the efficacy and safety of this approach in a clinically representative pig post-MI chronic heart failure model. First, pigs will undergo a coronary artery balloon occlusion and reperfusion MI, followed 4 weeks later by minimally invasive, transendocardial injection of CCPs + cECM, CCPs alone, cECM alone or sham. Contractility, chamber geometry, viability and strain analysis will be performed using quantitative magnetic resonance imaging. Detailed histopathology will be performed. A continuous ECG recorder will be implanted for arrhythmia surveillance. The primary efficacy endpoint will be change in ejection fraction from baseline to 3 months. Highly qualified investigators at the University of Wisconsin-Madison will partner with Fujifilm Cellular Dynamics Inc., Madison, WI (manufacturers of CCPs) and Cellular Logistics Inc., Sun Prairie, WI (manufacturer of cECM, also known as CellogicusTM) to ensure careful scientific rigor is applied for this Investigational New Drug (IND) enabling project. The design of this study has been carefully considered in accordance to FDA/CBER guidelines and will benefit from continued guidance through the Regenerative Medicine Innovation Catalyst to accelerate therapeutic product development and inform future human trials.