Committed Cardiac Progenitors to Remuscularize the Failing Ischemic Heart

项目摘要/摘要 由于心肌细胞和细胞外基质的破坏而导致的收缩心肌的损失 心肌梗塞(MI)的标志。大心肌梗死或反复心肌梗死的后果是渐进的 左心室增大，慢性心力衰竭和死亡。心脏移植可以挽救生命；然而， 严重的全身器官短缺阻碍了这种疗法的广泛采用。因此，心梗后心力衰竭仍在继续。 成为一个重大的公共卫生挑战。基于细胞的疗法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、骨骼肌的临床试验 成人心脏来源的细胞没有或只显示出轻微的好处。电池保持率差，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障碍。 我们提出了一种治疗方案，利用一群创新的人类重新肌化心肌。 IPSC来源的定向心脏祖细胞(CCP)与天然心脏成纤维细胞来源的组合 细胞外基质(CECM)，以改善细胞保留和修复受损的基质。CCP有一个 非凡的能力，成为心肌细胞，整合到受损的心肌中。CECM绑定到 治疗细胞，并改善它们在心脏组织中的滞留。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健康。 CCP和CCM都可以生产小规格、高规模的产品。 我们假设，肌肉内联合应用CCP和CECM将使肌肉化。 比单独使用任何一种产品都能更有效地改善心肌和改善心功能。为了检验这一假设， 我们将在一个具有临床代表性的猪急性心肌梗死后慢性心脏疾病中测量这种方法的有效性和安全性。 故障模型。首先，猪将接受冠状动脉球囊阻断和再灌注性心肌梗死，随后4周 随后经心内膜微创注射CCPS+CCM、单独注射CCPS、单独注射CCM或假手术。 收缩性能、腔室几何形状、生存能力和应变分析将使用定量磁力进行 磁共振成像。将进行详细的组织病理学检查。将植入一台连续的心电记录器 进行心律失常监测。主要疗效终点将是射血分数从基线改变为 三个月。 威斯康星大学麦迪逊分校的高素质调查人员将与富士胶片细胞公司合作 威斯康星州麦迪逊的Dynamic Inc.(CCP制造商)和威斯康星州Sun Prairie的蜂窝物流公司 (cECM制造商，也称为CellogicusTM)，以确保对此应用仔细的科学严谨性 研究性新药(IND)启动项目。这项研究的设计经过了仔细的考虑 符合FDA/CBER指南，并将受益于通过再生性 药物创新催化剂，以加快治疗产品的开发，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.