Cell Therapy for the Treatment of Acute Respiratory Distress Syndrome

描述(由申请人提供)：这是一项第一阶段-第二阶段快速通道申请的重新提交，用于急性呼吸窘迫综合征(ARDS)患者的临床使用。急性呼吸窘迫综合征定义为急性起病低氧血症、双侧肺浸润性病变和无房压高血压。一种新的和令人兴奋的可能性是使用细胞作为肺损伤治疗的一部分。我们和其他小组已经证明，外源性输注分离的间充质干细胞(B-MSC)可以预防炎症和肺损伤后的异常修复。这些和其他观察表明，B-MSC是一种潜在的安全和有效的肺损伤治疗干预措施。B-MSC作为治疗人类ARDS的细胞疗法的进展需要完成临床前研究和动物模型的验证。我们建议评估GMP产生的人骨髓来源的贴壁干细胞(MultiStem)在内毒素诱导的中重度ARDS绵羊模型中的治疗效果。据我们所知，目前还没有关于使用这种动物模型来评估ARDS细胞疗法效果的公开文献，这使得这些临床前研究具有独特性和高度新颖性。这项建议是麦高恩再生医学研究所、肺、过敏和重症护理部门以及匹兹堡大学心胸移植部门与Athersys，Inc.密切合作的结果，Athersys，Inc.是一家专门生产同种异体GMP级骨髓来源贴壁干细胞的生物技术公司，称为MultiStem。我们建议，学术界和产业界之间的合作将加速和验证人类GMP产生的多干细胞在ARDS患者中的使用。我们的团队拥有确保这一项目成功完成所需的基础设施和专业知识。我们的目标是完成获得研究性新药(IND)所需的必要的临床前研究。根据IND前与FDA的一次会议，他们的建议已被纳入当前的提案中：(确定经支气管或静脉注射MultiStem对脂多糖诱导的ARDS绵羊模型的生物学后果)；以及特定目标2(II期)，以在I期临床试验中证明MultiStem在ARDS患者中的安全性。

DESCRIPTION (provided by applicant): This is a resubmission of a Phase I-Phase II Fast-Track application for the clinical use of MultiStem in patients with acute respiratory distress syndrome (ARDS). ARDS is defined as acute onset hypoxemia, bilateral radiographic pulmonary infiltrates and lack of atrial pressure hypertension. A novel and exiting possibility is the use of cells as part of the therapy in lung injury. We and other groups have demonstrated that exogenous infusion of isolated mesenchymal stem cells (B-MSC) prevents inflammation and aberrant repair after lung injury. These and other observations suggest that B-MSC is a potentially safe and effective therapeutic intervention in lung injury. Progress toward B-MSC as a cell therapy for ARDS in humans requires completion of preclinical studies and validation in animal models. We propose to evaluate the therapeutic effect of a GMP-produced human adherent bone marrow derived stem cell (MultiStem) in a sheep model of endotoxin-induced moderate-severe ARDS. To our knowledge, there are no published references on the use of this animal model to evaluate the effect of cell therapies for ARDS, making these pre-clinical studies unique and highly novel. This proposal is the result of a close collaboration between the McGowan Institute of Regenerative Medicine, the Division of Pulmonary, Allergy and Critical Care, and the Division of Cardiothoracic Transplantation at the University of Pittsburgh with Athersys, Inc. a biotechnology company specialized in the generation of an allogeneic GMP-grade bone marrow derived adherent stem cells termed MultiStem. We propose that a partnership between academia and industry will accelerate and validate the use of human GMP-produced MultiStem in patients with ARDS. Our groups have the infrastructure and expertise required to assure successful completion of this project. Our goal is to complete the necessary pre-clinical studies required to obtain an Investigational New Drug (IND). Based on a pre-IND meeting with the FDA their suggestions have been incorporated in the present proposal: {Determination of the biological consequences of intrabronchial or intravenous delivery of MultiStem on the sheep model of LPS-induced ARDS}; and Specific Aim 2 (Phase II), to demonstrate the safety of MultiStem in patients with ARDS in a Phase I clinical trial.