Cell Based Therapy for Non-Ischemic Dilated Cardiomyopathy

描述（由申请人提供）： 本申请参与CCTRN提出的临床研究技能开发计划和I/II期随机临床试验，旨在评估特发性扩张型心肌病（IDCM）的新型细胞治疗策略的安全性和有效性，IDCM是心力衰竭（HF）、死亡和残疾的主要原因。这项试验将在IDCM的细胞治疗领域产生重大影响，作为产生持久和可持续改善心脏功能并引起逆转重塑的新方法。本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）在HF患者中使用基于导管的系统可以安全有效地进行心肌内细胞递送，2）骨髓源性间充质干细胞（MSC）耐受性良好，植入损伤组织，并刺激内源性心脏干细胞（CSC）增殖和分化。因此，待测试的假设是，相对于单独使用MSC，组合CSC和MSC将增强治疗功效。将使用心脏MRI评估表型水平的作用机制，以测量局部和整体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。MSC疗法的细胞作用机制将通过测量内源性CSC增殖和分化的能力来评估。将获得肌内膜活检并测试其产生内源性CSC的能力。我们的团队在缺血性和非缺血性HF患者中导管输送MSC方面具有丰富的经验。因此，这项研究是及时的，有必要的，并可能通过解决IDCM患者未满足的需求产生重大的健康影响。该计划将通过测试新的治疗方法，结合两种具有生物学协同特性的细胞类型，在该领域开辟新天地。总之，这些目标将促进我们对IDCM细胞治疗的理解，特别强调患者选择参数，细胞递送策略和新型细胞制剂的影响。

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.