Stem Cells for Dilated Cardiomyopathy

描述（由申请人提供）：特发性扩张型心肌病（IDCM）是充血性心力衰竭的主要原因，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，这种疾病是基于细胞的治疗的主要候选者。扩张型心肌病的主要表型是心室增大、重塑，舒张末期和收缩末期容积增加，射血分数降低，收缩和舒张功能受损。基于细胞的治疗作为一种新的方法具有很大的希望，可以持久和可持续地改善功能障碍的心脏，并引起逆转重塑。如果这些效果可以在临床上建立和优化，那么对于许多患有扩张型心肌病的患者来说，改善临床结果的潜力是巨大的。我们的团队在缺血性心肌病患者中导管输送骨髓间充质干细胞方面拥有丰富的经验，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，心脏再生细胞治疗策略引起了大量的科学和公众兴趣。该试验目前已获得FDA批准，研究者发起的IND编号为BB-14419（PI：Hare），因此准备启动。该提案的具体目标是：1.探讨骨髓间充质干细胞（MSC）治疗原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同种异体MSC治疗，采用经血管内导管输送系统经皮输送。2.比较两种不同的骨髓制剂-同种异体与自体骨髓源性间充质干细胞（MSC）-在非缺血性心肌病患者中的安全性和有效性。将使用心脏磁共振成像（MRI）评估表型水平的作用机制，以测量MI大小、局部和整体LV功能、组织纤维化和组织灌注。将进行事后分析，以检验细胞形态、细胞表面标志物和细胞集落生长潜力的体外评估可预测个体患者细胞改善心脏指标的能力的假设。3.通过测量内源性心脏干细胞增殖和分化的能力，评估MSC治疗的细胞作用机制。将从入组本试验的患者中获得肌内膜活检，并检测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.