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

描述（由申请人提供）：急性肺损伤（ALI）和休克患者的死亡率很高（30-40%）。因此，需要创新疗法来改善这些患者的临床结局。我们的研究小组和其他研究人员报告说，骨髓来源的间充质干细胞（MSC）减少肺和非肺器官损伤和死亡率在临床前模型的ALI和败血症。我们的研究小组还发现，静脉内MSC在离体灌注的人肺制剂中可有效逆转ALI。MSC的有益作用主要通过抗炎细胞因子、生长因子、血管生成素-1和其他分子的旁分泌释放来解释，这些分子恢复受损肺中内皮和内皮屏障的正常功能，并且还增强修复。MSC还产生抑制细菌生长的抗菌产品。同种异体人MSC已被用于2,000多名患有各种临床疾病的患者，没有发生重大不良事件。因此，我们提出了一项II期临床试验，该试验将招募60名患有ALI和休克的成年患者参加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。除严重创伤外，患者将继发于所有临床原因的ALI。这些患者将在五所大学的医学中心（UCSF、斯坦福大学、匹兹堡、佛蒙特州和哈佛）招募。MSC治疗的患者将接受由NHLBI支持的明尼苏达大学应用治疗学项目生产的临床级MSC。该试验将测试以下三个假设。假设1：与安慰剂治疗相比，人MSC将降低ALI的严重程度，如通过4分复合ALI评分所量化的。假设2：与安慰剂治疗相比，人MSC治疗将减少通过布鲁塞尔器官评分测量的非肺器官衰竭。假设3：与安慰剂治疗相比，人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，以提供对人类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20万患者受到影响。这项临床试验将测试来自正常成人（年龄18-30岁）的骨髓间充质干细胞作为一种新疗法的潜在治疗价值，以降低急性肺损伤和急性呼吸衰竭重症患者的死亡率。

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.