Cell Therapy for the Treatment of Acute Respiratory Distress Syndrome

描述（由申请人提供）：这是一份关于MultiStem在急性呼吸窘迫综合征（ARDS）患者临床应用的i - II期快速通道申请的重新提交。ARDS定义为急性低氧血症，双侧肺浸润和无房压高血压。利用细胞作为肺损伤治疗的一部分是一种新颖而令人兴奋的可能性。我们和其他研究小组已经证明，外源性输注分离的间充质干细胞（B-MSC）可以防止肺损伤后的炎症和异常修复。这些和其他观察结果表明，B-MSC是一种潜在的安全有效的肺损伤治疗干预措施。B-MSC作为人类ARDS细胞疗法的进展需要完成临床前研究和动物模型验证。我们建议评估gmp生产的人贴壁骨髓来源干细胞（MultiStem）在内毒素诱导的中重度ARDS羊模型中的治疗效果。据我们所知，目前还没有发表过关于使用这种动物模型来评估细胞治疗ARDS效果的文献，这使得这些临床前研究具有独特性和高度新颖性。该提案是匹兹堡大学McGowan再生医学研究所、肺部、过敏和危重症护理部门以及心肺移植部门与Athersys， Inc.（一家专门从事生产称为MultiStem的同种异体gmp级骨髓来源贴壁干细胞的生物技术公司）密切合作的结果。我们建议学术界和工业界之间的合作将加速和验证人类gmp生产的MultiStem在ARDS患者中的使用。我们的团队拥有确保该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）所需的必要临床前研究。基于与FDA的ind前会议，他们的建议已被纳入本提案：{确定多管注射剂对lps诱导的ARDS羊模型的生物学后果}；和Specific Aim 2 （II期），在I期临床试验中证明MultiStem对ARDS患者的安全性。

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.