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）和休克的患者死亡率很高（30-40%）。因此，需要创新的治疗方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道，骨髓来源的间充质干细胞（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静脉注射间充质干细胞对体外灌注的人肺制剂中ALI的逆转是有效的。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等分子，恢复损伤肺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微生物产品。同种异体人骨髓间充质干细胞已应用于2000多名患有各种临床疾病的患者，未发生重大不良事件。因此，我们建议进行一项II期临床试验，将60名患有ALI和休克的成年患者纳入一项多中心、安慰剂对照、2:1的MSC（40例）和安慰剂（20例）随机试验。患者继发于除重大创伤外的所有临床原因。这些患者将在五所大学医学中心（加州大学旧金山分校、斯坦福大学、匹兹堡大学、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将降低ALI的严重程度，这是由4点ALI综合评分量化的。假设2：根据布鲁塞尔器官评分，与安慰剂治疗相比，人类骨髓间充质干细胞治疗将减少非肺器官衰竭。假设3：与安慰剂治疗相比，人间充质干细胞在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，这两项研究都将在临床试验中使用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（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。这项临床试验将测试来自正常成人（18-30岁）骨髓间充质干细胞的细胞治疗作为一种降低急性肺损伤和急性呼吸衰竭危重患者死亡率的新疗法的潜在治疗价值。

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.