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世界首次利用干细胞治疗再生出健康心肌

来自Cedars-Sinai心脏研究所的临床试验结果表明,给病人注入他们自己的心脏来源细胞有助于受损心脏再生出健康心肌。

心脏病发作会在心肌留下疤痕。对接受实验性干细胞治疗的病人而言,这种疤痕大小显著地减少,而且健康心肌发生相当大的增加。

在接受干细胞治疗一年后,接受细胞治疗的病人心脏中疤痕大小减少24%到12%不等(平均下降率约50%)。而没接受干细胞治疗的对照组病人心脏中疤痕大小没有减小。该研究的最初目标是证实其安全性,也想寻找关于这种治疗方法可能溶解疤痕与再生受损心肌的证据。尽管心脏病病人细胞治疗试验已有十年时间,但是之前一直没有取得这么好的结果。过去,我们能做的所有事情就是通过迅速打开被阻塞的动脉来最小化心脏损伤。现在,此研究表明存在一种再生治疗法,这种疗法确实可能逆转心脏病发作引起的损伤。

名为CADUCEUS(CArdiosphere-Derived aUtologous stem CElls to Reverse ventricUlar dySfunction)的临床试验是FDA批准并由美国国家心脏、肺和血液研究所支持的I期研究的一部分。在2009年,作为此项研究的最初部分,Marbán和他的研究团队世界上第一次实现用病人自己的心脏组织来培养特殊的心脏干细胞。然后,这种干细胞被注射回病人心脏中来努力修补心脏病发作导致的心脏受损和再生出健康心肌。

与此项研究相关的培养心脏来源干细胞的过程早期是由Marbán开发的,当时他是约翰·霍普金斯大学的教职人员。约翰·霍普金斯大学已申请了这种过程的专利,并已许可给一家Marbán博士有财务利益的公司。那家公司没有提供资金用于支持这项临床研究。所有资金来源于美国国家卫生研究院和Cedars-Sinai医学中心。

Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial

Raj R Makkar, Rachel R Smith , Ke Cheng, Konstantinos Malliaras , Louise EJ Thomson, Daniel Berman , Lawrence SC Czer, Linda Marbán, Adam Mendizabal , Peter V Johnston, Stuart D Russell, Karl H Schuleri , Albert C Lardo , Gary Gerstenblith , Eduardo Marbán

ABSTRACT Background:Cardiosphere-derived cells (CDCs) reduce scarring after myocardial infarction, increase viable myocardium, and boost cardiac function in preclinical models. We aimed to assess safety of such an approach in patients with left ventricular dysfunction after myocardial infarction. Methods: In the prospective, randomised CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial, we enrolled patients 2-4 weeks after myocardial infarction (with left ventricular ejection fraction of 25-45%) at two medical centres in the USA. An independent data coordinating centre randomly allocated patients in a 2:1 ratio to receive CDCs or standard care. For patients assigned to receive CDCs, autologous cells grown from endomyocardial biopsy specimens were infused into the infarct-related artery 1·5-3 months after myocardial infarction. The primary endpoint was proportion of patients at 6 months who died due to ventricular tachycardia, ventricular fibrillation, or sudden unexpected death, or had myocardial infarction after cell infusion, new cardiac tumour formation on MRI, or a major adverse cardiac event (MACE; composite of death and hospital admission for heart failure or non-fatal recurrent myocardial infarction). We also assessed preliminary efficacy endpoints on MRI by 6 months. Data analysers were masked to group assignment. This study is registered with ClinicalTrials.gov,NCT00893360. Findings: Between May 5, 2009, and Dec 16, 2010, we randomly allocated 31 eligible participants of whom 25 were included in a per-protocol analysis (17 to CDC group and eight to standard of care). Mean baseline left ventricular ejection fraction (LVEF) was 39% (SD 12) and scar occupied 24% (10) of left ventricular mass. Biopsy samples yielded prescribed cell doses within 36 days (SD 6). No complications were reported within 24 h of CDC infusion. By 6 months, no patients had died, developed cardiac tumours, or MACE in either group. Four patients (24%) in the CDC group had serious adverse events compared with one control (13%; p=1·00). Compared with controls at 6 months, MRI analysis of patients treated with CDCs showed reductions in scar mass (p=0·001), increases in viable heart mass (p=0·01) and regional contractility (p=0·02), and regional systolic wall thickening (p=0·015). However, changes in end-diastolic volume, end-systolic volume, and LVEF did not differ between groups by 6 months. Interpretation:We show intracoronary infusion of autologous CDCs after myocardial infarction is safe, warranting the expansion of such therapy to phase 2 study. The unprecedented increases we noted in viable myocardium, which are consistent with therapeutic regeneration, merit further assessment of clinical outcomes. Funding: US National Heart, Lung and Blood Institute and Cedars-Sinai Board of Governors Heart Stem Cell Center