Stem Cells for Dilated Cardiomyopathy

描述（申请人提供）：特发性扩张型心肌病（IDCM）是导致充血性心力衰竭的主要原因，可通过心力衰竭和心源性猝死导致死亡和残疾，约占心脏移植手术的50%。因此，这种疾病是细胞治疗的主要候选者。扩张型心肌病的主要表型是心室扩大，重构，舒张末期和收缩末期体积增加，射血分数降低，收缩和舒张功能受损。细胞疗法作为一种新方法，在功能失调的心脏中产生持久和可持续的改善，并引起反向重构，具有很大的前景。如果这些效果可以在临床上建立和优化，对于许多患有扩张型心肌病的患者来说，有巨大的潜力来改善临床结果。我们的团队在缺血性心肌病患者骨髓间充质干细胞的导管输送方面有丰富的经验，现在准备在非缺血性心肌病患者中测试这一令人兴奋的临床假设。基于临床前、转化和早期临床研究，有大量的科学和公众对心脏再生细胞治疗策略感兴趣。该试验目前已获得FDA批准，IND号为BB-14419 (PI: Hare)，因此准备启动。本建议的具体目的是：1。目的：探讨骨髓间充质干细胞（MSC）治疗特发性扩张型心肌病的安全性和有效性。我们将随机比较自体和异体骨髓间充质干细胞经皮给药和经心内膜导管给药系统。2. 比较异体骨髓与自体骨髓间充质干细胞（MSCs）两种不同骨髓制剂在非缺血性心肌病患者中的安全性和有效性。在表型水平上的作用机制将通过心脏磁共振成像（MRI）来评估心肌梗死大小、局部和全局左室功能、组织纤维化和组织灌注。将进行事后分析，以验证细胞形态、细胞表面标记物和细胞集落生长潜力的体外评估可能预测个体患者细胞改善心脏指标的能力。3. 通过测量内源性心脏干细胞增殖和分化的能力来评估MSC治疗的细胞作用机制。将对参加本试验的患者进行心内膜活检，并测试其产生内源性心脏干细胞的能力。

DESCRIPTION (provided by applicant): Idiopathic dilated cardiomyopathy (IDCM) is a leading cause of congestive heart failure, produces death and disability via heart failure and sudden cardiac death, and accounts for ~50% of heart transplants performed. As such this disorder is a lead candidate for cell-based therapy. The primary phenotype of dilated cardiomyopathy is an enlarged, remodeled ventricle with increases in end-diastolic and end-systolic volumes, reduced ejection fraction, and impaired contractile and diastolic function. Cell-based therapy holds great promise as a new approach to produce durable and sustainable improvements in dysfunctional hearts and to cause reverse remodeling. If these effects can be clinically established and optimized, there is enormous potential for improving clinical outcomes for the many patients suffering from dilated cardiomyopathy. Our group has extensive experience with catheter delivery of bone-marrow derived mesenchymal stem cells in patients with ischemic cardiomyopathy and is now poised to test this exciting clinical hypothesis in patients with non-ischemic cardiomyopathy. There is substantial scientific and public interest for cardiac regenerative cell therapy strategies, based on pre-clinical, translational, and early clinical studies. This trial is currently approved by the FDA under investigator initiated IND number BB-14419 (PI: Hare), and is therefore ready to be initiated. The specific aims of this proposal are: 1. To establish the safety and efficacy of bone marrow derived mesenchymal stem cell (MSC) therapy for patients with idiopathic dilated cardiomyopathy. We will perform a randomized comparison of autologous and allogeneic MSC therapy employing percutaneous delivery with a transendocardial catheter delivery system. 2. To compare two different bone marrow preparations - allogeneic vs. autologous bone marrow derived mesenchymal stem cells (MSCs) - for safety and efficacy in patients with non-ischemic cardiomyopathy. The mechanism of action at a phenotypic level will be assessed using cardiac magnetic resonance imaging (MRI) to measure MI size, regional and global LV function, tissue fibrosis, and tissue perfusion. A post-hoc analysis will be performed to test the hypothesis that in vitro assessments of cell morphology, cell surface markers, and cell colony growth potential may predict the ability of an individual patient's cells to improve the cardiac measures. 3. To assess cellular mechanisms of action of MSC therapy by measuring the capacity for endogenous cardiac stem cell proliferation and differentiation. Endomyocardial biopsies will be obtained from the patients enrolled in this trial and tested for their capacity to yield endogenous cardiac stem cells.