Cell Based Therapy for Non-Ischemic Dilated Cardiomyopathy

描述(由申请人提供)： 本次申请参加CCTRN提出了临床研究技能发展计划和L/11期随机临床试验，评估基于细胞的新治疗策略对特发性扩张型心肌病的安全性和有效性，特发性扩张型心肌病是导致心力衰竭、死亡和残疾的主要原因。这项试验将在IDCM的基于细胞的治疗领域产生重大影响，作为产生持久和可持续的心功能改善和逆转重塑的新方法。这项试验建立在广泛的临床前和临床工作的坚实基础上，证明：1)心衰患者使用导管系统可以安全有效地进行心肌内细胞输送，2)骨髓间充质干细胞(MSCs)具有良好的耐受性，可以移植到受损组织中，并刺激内源性心脏干细胞(CSC)的增殖和分化。因此，需要检验的假设是，与单独使用MSCs相比，联合使用CSCs和MSCs将提高治疗效果。表型水平的作用机制将使用心脏MRI来评估，以测量局部和整体左心功能、组织纤维化和组织灌注量。之后的分析将被用来检验细胞形态、细胞表面标志物和细胞集落生长潜力的体外评估可以预测单个患者细胞改善心脏测量的能力的假设。MSC治疗的细胞机制将通过测量内源性CSC的增殖和分化能力来评估。心内膜心肌活检将获得并检测其产生内源性CSCs的能力。我们小组在缺血性和非缺血性心力衰竭患者的导管移植间充质干细胞方面有丰富的经验。因此，这项研究是及时的、有根据的，并可能通过解决IDCM患者未得到满足的需求而对健康产生重大影响。该计划将通过测试新的治疗方法在领域中开辟新的天地，将两种细胞类型结合在一起，共同具有生物学上证明的协同特性。总而言之，这些目标将促进我们对IDCM基于细胞的治疗的理解，特别强调患者选择的参数、细胞输送策略和新细胞配方的影响。

DESCRIPTION (provided by applicant): This application to participate in the CCTRN proposes clinical research skills development program and phase l/ll randomized clinical trial evaluating the safety and efficacy of novel cell-based therapeutic strategy for idiopathic dilated cardiomyopathy (IDCM), a leading cause of heart failure (HF), death and disability. This trial will have major impact in the field of cell-baed therapy for IDCM as new approach to produce durable and sustainable improvements in heart function and to cause reverse remodeling. This trial is built on solid foundation of extensive preclinical and clinical work demonstrating that: 1) intramyocardial cell delivery can be safely and effectively performed using catheter based system in HF patients, and 2) bone marrow-derived mesenchymal stem cells (MSCs) are well tolerated, engraft in injured tissues, and stimulate endogenous cardiac stem cell (CSC) proliferation and differentiation. Accordingly, the hypothesis to be tested is that combining CSCs and MSCs will enhance the therapeutic efficacy relative to use of MSCs alone. The mechanism of action at phenotypic level will be assessed using cardiac MRI to measure regional and global LV function, tissue fibrosis, and tissue perfusion. 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 ability of individual patient's cells to improve cardiac measures. Cellular mechanisms of action of MSC therapy will be assessed by measuring capacity for endogenous CSC proliferation and differentiation. Endomyocardial biopsies will be obtained and tested for their capacity to yield endogenous CSCs. Our group has extensive experience with catheter delivery of MSCs in patients with ischemic and non-ischemic HF. Accordingly, this study is timely, warranted, and may have major health impact by addressing unmet need in IDCM patients. This program will break new ground in field by testing novel therapeutic approach, combining two cell types that together have synergistic properties demonstrated biologically. Together, these aims will advance our understanding of cell-based therapy for IDCM, with specific emphasis placed upon parameters of patient selection, cell delivery strategies, and the impact of novel cell formulations.