Allogeneic Human Mesenchymal Stem Cells for the Treatment of Acute Lung Injury

同种异体人间充质干细胞治疗急性肺损伤

基本信息

批准号：
8144663
负责人：
MICHAEL A. MATTHAY
金额：
$ 111.71万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8144663
关键词：
Academic Medical Centers Acute Acute Lung Injury Acute respiratory failure Adult Adverse event Affect Age Allogenic Ancillary Study Angiopoietin-1 Anti-Inflammatory Agents Anti-inflammatory Bacteria Bone Marrow Bronchoalveolar Lavage Fluid Cell Therapy Clinical Clinical Trials Critical Illness Disease Enrollment Growth Growth Factor Human Injury Innovative Therapy Instruction Intravenous Lung Measures Mesenchymal Stem Cells Minnesota National Heart, Lung, and Blood Institute Organ Organ failure Outcome Patients Phase II Clinical Trials Placebo Control Placebos Plasma Pre-Clinical Model Preparation Recruitment Activity Reporting Research Research Personnel Safety Sampling Secondary to Sepsis Severities Shock Testing Therapeutic Trauma United States Universities Vermont antimicrobial cytokine improved injured insight lung injury mortality novel paracrine programs randomized trial repaired

项目摘要

DESCRIPTION (provided by applicant): Patients who present with acute lung injury (ALI) and shock have a high mortality (30-40%). Therefore, innovative therapies are needed to improve clinical outcomes in these patients. Our research group and other investigators have reported that bone marrow-derived mesenchymal stem cells (MSC) reduce pulmonary and non-pulmonary organ injury and mortality in preclinical models of ALI and sepsis. Our research group has also found that intravenous MSC are effective for reversing ALI in an ex vivo perfused human lung preparation. The beneficial effects of MSC are explained primarily by the paracrine release of anti-inflammatory cytokines, growth factors, angiopoietin-1 and other molecules that restore normal function of the endothelial and endothelial barriers in the injured lung and also enhance repair. MSC also produce anti-microbial products that inhibit bacteria growth. Allogeneic human MSC have been administered to over 2,000 patients with a variety of clinical disorders without major adverse events. Therefore, we are proposing a phase II clinical trial that will enroll 60 adult patients with ALI and shock in a multi-center, placebo- controlled, 2:1 randomized trial of MSC (40 patients) versus placebo (20 patients). Patients will have ALI secondary to all clinical causes except major trauma. The patients will be recruited at five university medical centers (UCSF, Stanford, Pittsburgh, Vermont, and Harvard). The MSC-treated patients will receive clinical- grade MSC produced at the University of Minnesota Program in Applied Therapeutics, supported by the NHLBI. The trial will test the following three hypotheses. Hypothesis 1: Compared to placebo treatment, human MSC will reduce the severity of ALI as quantified by the 4-point composite ALI score. Hypothesis 2: Compared to placebo treatment, human MSC treatment will reduce non-pulmonary organ failures as measured by the Brussels Organ Score. Hypothesis 3: Compared to placebo treatment, human MSC will have an acceptable safety profile in patients with ALI. We are also proposing two ancillary studies, both of which will use samples of plasma and bronchoalveolar lavage fluid (BALF) from patients in the clinical trial to provide mechanistic insights into how human MSC reduce lung injury and non-pulmonary organ failure. RELEVANCE (See instructions): Acute lung Injury is a major cause of acute respiratory failure that affects 200,000 patients in the United States alone. This clinical trial will test the potential therapeutic value of cell-based therapy with bone marrow derived mesenchymal stem cells from normal adults (age 18-30) as a novel therapy to reduce mortality in critically ill patients with acute lung injury and acute respiratory failure.

描述（由申请人提供）：患有急性肺损伤（ALI）和休克的患者死亡率很高（30-40%）。因此，需要创新疗法来改善这些患者的临床结果。我们的研究小组和其他研究人员报告说，骨髓间充质干细胞 (MSC) 可以减少 ALI 和脓毒症临床前模型中的肺和非肺器官损伤和死亡率。我们的研究小组还发现，在离体灌注的人肺制剂中，静脉注射 MSC 可有效逆转 ALI。 MSC 的有益作用主要是通过旁分泌释放抗炎细胞因子、生长因子、血管生成素-1 和其他分子来恢复受损肺部内皮和内皮屏障的正常功能并增强修复。 MSC 还生产抑制细菌生长的抗菌产品。同种异体人类 MSC 已被用于 2,000 多名患有各种临床疾病的患者，没有出现重大不良事件。因此，我们提议开展一项 II 期临床试验，将招募 60 名患有 ALI 和休克的成人患者，进行 MSC（40 名患者）与安慰剂（20 名患者）的多中心、安慰剂对照、2:1 随机试验。除重大外伤外，患者会因所有临床原因继发 ALI。这些患者将在五个大学医疗中心（加州大学旧金山分校、斯坦福大学、匹兹堡、佛蒙特州和哈佛大学）招募。接受 MSC 治疗的患者将接受由 NHLBI 支持的明尼苏达大学应用治疗项目生产的临床级 MSC。该试验将检验以下三个假设。假设 1：与安慰剂治疗相比，人类 MSC 将减轻 ALI 的严重程度（按 4 点综合 ALI 评分量化）。假设 2：与安慰剂治疗相比，人类 MSC 治疗将减少根据布鲁塞尔器官评分衡量的非肺器官衰竭。假设 3：与安慰剂治疗相比，人类 MSC 在 ALI 患者中具有可接受的安全性。我们还提出了两项辅助研究，这两项研究都将使用临床试验中患者的血浆和支气管肺泡灌洗液 (BALF) 样本，以提供人类 MSC 如何减少肺损伤和非肺器官衰竭的机制见解。相关性（参见说明）：急性肺损伤是急性呼吸衰竭的主要原因，仅在美国就有 200,000 名患者受到影响。该临床试验将测试使用来自正常成人（18-30岁）的骨髓来源的间充质干细胞作为一种新疗法的细胞疗法的潜在治疗价值，以降低患有急性肺损伤和急性呼吸衰竭的危重患者的死亡率。