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，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现形式是扩大的、重塑的心室，舒张末和收缩末期容量增加，射血分数降低，收缩和舒张期功能受损。基于细胞的治疗作为一种新的方法具有很大的前景，可以对功能障碍的心脏产生持久和可持续的改善，并导致反向重塑。如果这些效应能够在临床上得到确立和优化，那么对于许多患有扩张型心肌病的患者来说，将有巨大的潜力改善临床结果。我们小组在缺血性心肌病患者的骨髓间充质干细胞导管输送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说。在临床前、转化期和早期临床研究的基础上，心脏再生细胞治疗策略受到了科学和公众的广泛关注。这项试验目前由食品和药物管理局批准，由调查员发起，IND编号BB-14419(PI：HARE)，因此准备启动。本建议的具体目的是：1.确定骨髓间充质干细胞(MSC)治疗特发性扩张型心肌病的安全性和有效性。我们将对采用经皮给药和经心内膜导管给药系统的自体和同种异体间充质干细胞治疗进行随机比较。2.比较异基因和自体骨髓间充质干细胞(MSCs)两种不同的骨髓制剂治疗非缺血性心肌病患者的安全性和有效性。表型水平的作用机制将使用心脏磁共振成像(MRI)来评估，以测量MI大小、局部和整体左心功能、组织纤维化和组织灌注量。对细胞形态、细胞表面标记物和细胞集落生长潜力的体外评估可以预测单个患者细胞改善心脏测量的能力，这一假说将进行后期分析。3.通过检测MSC对内源性心肌干细胞的增殖和分化能力，探讨MSC治疗的细胞机制。心内膜心肌活检将从参加这项试验的患者身上获得，并测试他们产生内源性心脏干细胞的能力。 公共卫生相关性：这项临床研究将解决一个重要的临床需求，即调查治疗心力衰竭的新的和有前途的疗法，心力衰竭是导致心血管死亡和残疾的主要原因之一。拟议的研究将阐明心脏组织修复和再生的新机制。

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. PUBLIC HEALTH RELEVANCE: This clinical study will address a significant clinical need, namely the investigation of new and promising therapies for heart failure, one of the leading causes of cardiovascular death and disability. The proposed studies will elucidate new mechanisms of repair and regeneration of heart tissue.