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.
Public Health Relevance Statement: Public Health Relevance: Acute Respiratory Distress Syndrome (ARDS) is a very common clinical entity and a major cause of morbidity and mortality in the critical care setting with limited therapeutic options. The development of cell therapy for the treatment of ARDS will provide a novel therapeutic for this significant disease.
Project Terms: Academia; Acute; Adult Respiratory Distress Syndrome; Allogenic; Alveolar; Animal Model; Animals; Attenuated; base; Berlin; Bilateral; Biological; Biological Markers; Biotechnology; Blood capillaries; Bone Marrow; capillary; Categories; Cell Therapy; cell type; Cells; Clinic; Clinical; clinical application; Clinical Protocols; Clinical Trials; Collaborations; comparative efficacy; Conduct Clinical Trials; Critical Care; Data; Development; Disease; Dose; Elements; Endotoxins; Enrollment; experience; Gases; Generations; Goals; Heart Atrium; hemodynamics; Human; Hypersensitivity; Hypertension; Hypoxemia; improved; Industry; Inflammation; Inflammatory Response; Infusion procedures; Institutes; Intravenous; Investigational Drugs; Investigational New Drug Application; Kidney; Liver; Lung; lung injury; Lung Injury, Acute; Measurement; meetings; Mesenchymal; Mesenchymal Stem Cells; Modeling; Morbidity - disease rate; Mortality Vital Statistics; Mus; novel; novel therapeutics; Pancreas; Patients; Phase; Phase I Clinical Trials; Physiological; preclinical study; pressure; prevent; Process; protective effect; public health relevance; Publishing; pulmonary function; Recommendation; Regenerative Medicine; repaired; Research Infrastructure; Research Personnel; research study; Role; Safety; Saline; Series; Severities; Sheep; Stem cells; Stromal Cells; Suggestion; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Toxic effect; Translations; Transplantation; Universities; Validation
