Executive Summary The applicant proposes to establish a disease team which will focus on using mesenchymal stem cells (MSC) as a cellular therapy for idiopathic pulmonary fibrosis (IPF), a progressive lung disease which generally results in death within 5 years of diagnosis. The disease is characterized by uncontrolled proliferation and metabolism of lung fibroblasts and although the molecular etiology of IPF remains unclear, current evidence is consistent with a model in which damaged lung epithelial cells release inflammatory mediators which act in part to stimulate proliferation of fibroblasts and hence the scarring in the lung seen in IPF. The proposed clinical application of MSC in the setting of IPF is based on the beneficial effects of MSC administration in various rodent models of lung disease. All reviewers had concerns about the maturity of the concept. Although MSCs have been shown to lessen the fibrotic response in animal models of IPF, and have also been used in clinical trials for the treatment of inflammatory bowel disease, graft versus host disease, myocardial infarction and avascular necrosis of bone, the mechanisms by which MSCs confer protection against injury are not well understood in any of these settings. One reviewer felt that extensive preclinical studies, ideally involving larger animal models if possible, should be performed as a prerequisite for clinical application to provide objective data on cell dose, toxicity, and route of administration, as well as to explore the underlying mechanisms for the apparent beneficial effects of MSCs in this setting. The planning process would help to define the cells, route of administration, and best subjects for potential trials. One reviewer noted that a commercial source of MSCs is being tested in current clinical trials, including a planned trial for IPF, and questioned whether this proposed work would then be duplicative or better directed to another cell therapy target. This reviewer commented that much of the proposal was focused on producing GMP-grade MSCs, with no mention of collaborating with companies already doing this work. Reviewers were of different opinions about the PI’s track record and therefore his/her ability to lead a large, multidisciplinary team. The PI is a well established physician-scientist with some 17 years of continuous peer-reviewed funding in lung research. The PI is at the forefront of initiatives for cellular therapies for the treatment of lung disease, and in the role as Co-Chief of the Division of Pulmonary and Critical Care Medicine he/she has promoted the development of a research center to expand opportunities for clinical lung research. One reviewer felt that this investigator is ideally positioned to lead a Disease Team of the nature described in the present application. However, another reviewer noted that the PI has worked with smaller teams of researchers in laboratory based studies of lung injury at the applicant institution, but has no prior experience leading multidisciplinary collaborative projects. The proposed planning primarily is focused on details surrounding the production, upscaling and validation of MSCs, the development of standard operating procedures (SOPs) to produce MSCs, the development a single clinical trial to treat IPF with MSCs and to administer the MSCs. There is little discussion of the larger scope, broader or longer term goals for the program. A core group of investigators (PI and two collaborators) have been identified who will, in this initial proposal, determine which partnerships between other participating investigators are deemed most feasible (based on expertise, proximity, etc.). Existent collaborations will be utilized and additional collaborators with appropriate skills in stem cell research, regulatory affairs and GLP/GMP have expressed willingness to collaborate/participate. In summary, reviewers’ concerns over the lack of understanding of the mechanism, lack of validation in large animal models and the absence of discussion of (or linkage to) the clinical efforts already underway with a commercially available source of MSCs dampened the enthusiasm for this proposal. Reviewer Synopsis The applicant proposes to establish a disease team which will focus on using mesenchymal stem cells (MSC) as a cellular therapy for idiopathic pulmonary fibrosis (IPF) a progressive lung disease which generally results in death within 5 years of diagnosis. The disease is characterized by uncontrolled proliferation and metabolism of lung fibroblasts an although the molecular etiology of IPF remains unclear, current evidence is consistent with a model in which damaged lung epithelial cells release inflammatory mediators which act in part to stimulate proliferation of fibroblasts and hence the scarring in the lung seen in IPF. The proposed clinical application of MSC in the setting of IPF is based on the beneficial effects of MSC administration in various rodent models of lung disease. Reviewer One Comments Concept: The disease target, idiopathic pulmonary fibrosis is a severe condition of unknown cause. Some evidence exists in injury models in animals that administration of bone-marrow derived mesenchymal cells may ameliorate the condition. The plan in this proposal is to explore the development of a clinical program to address this disorder. A concern is whether this disease area is sufficiently “mature” for likely success with MSC administration. Based on bone marrow transplant (BMT) work, the PI suggests that MSCs might be administrated intravenously to patients with advanced lung disease in a trial. The planning process would help to define the cells, route of administration, and best subjects for potential trials. Principal Investigator: The PI, a Professor of Medicine at USC, is an established investigator in the pulmonary field with expertise in fibrotic lung disease. The PI is an appropriate leader for this disease effort. Planning Approach: The PI has assembled a team of stem cell investigators (at UCLA and USC) with expertise in BMT as well as regulatory aspects (GMP etc). The planning team is already engaged and the steps outlined for planning seem appropriate. Reviewer Two Comments Concept: These investigators propose to create a disease team to use allogeneic human mesenchymal stem cells (MSCs) to treat Idiopathic Pulmonary Fibrosis (IPF). IPF is a poorly understood, progressive disease characterized by uncontrolled fibroblast proliferation in lung tissue leading to progressive respiratory failure and death, usually within 5 years of diagnosis. The etiology is not known and may be multifactorial. There is no effective treatment. In experimental animal models, inflammation appears to mediate some of the pathogenesis of pulmonary fibrosis. MSCs have been shown to lessen the fibrotic response in animal models of IPF and have are also in clinical trials for the treatment of inflammatory bowel disease, graft versus host disease, myocardial infarction and avascular necrosis of bone. The mechanisms by which MSCs confer protection against injury are not well understood in any of these settings. One question that is not addressed in this proposal is the fact that a commercial source of MSCs (Osiris) is being tested in current clinical trials, including a planned trial for IFP. Would this work, then be duplicative or better directed to another cell therapy target? Principal Investigator: The PI is a professor of medicine at USC with extensive training in pulmonary medicine and critical care. She recently established a Center for Lung Research at USC, although her role in that program is not clearly delineated. She has worked with smaller teams of researchers in laboratory based studies of lung injury at USC. While qualified to lead this team, this would be her first experience bringing together a study group of this magnitude. Planning Approach: The proposed planning primarily is focused on details surrounding the production, upscaling and validation of MSCs, the development of standard operating procedures (SOPs) to produce MSCs, the development a single clinical trial to treat IPF with MSCs and to administer the MSCs. There is little discussion of the larger scope, broader or longer term goals for the program. Reviewer Three Comments Concept: MSC have been shown to have anti-inflammatory effects in vitro and in various pre-clinical models. This property together with apparent evidence of “trophic” effects on endogenous tissue cells has led to clinical application in a range of settings including cardiac disease. Although there are studies by other which have shown an apparent reduction in pulmonary fibrosis following MSC administration in animal models of lung disease, the molecular pathogenesis of IPF is not well understood and there is concern about clinical application of MSC in this setting. Extensive preclinical studies, ideally involving larger animal models if possible should be performed as a prerequisite for clinical application to provide objective data on cell dose, toxicity, etc., as well as to explore the underlying mechanisms for the apparent beneficial effects of MSC in this setting. Principal Investigator: The PI Dr Borok is a well established Physician-Scientist with some 17 years of continuous peer-reviewed funding in lung research. She is at the forefront of initiatives for cellular therapies for the treatment of lung disease and in her role as Co-Chief of the Division of Pulmonary and Critical Care Medicine she has promoted the development of a Center for Lung Research to expand opportunities for clinical lung research. Her experience and track record suggest Dr Borok is ideally positioned to lead a Disease Team of the nature described in the present application. Planning Approach: A well reasoned systematic approach the development of the planning process is evident. A core group of investigators (PI + Drs Luzko and Liebler) have been identified who will, in this initial proposal, determine which partner ships between other participating investigators are deemed most feasible (based on expertise, proximity, etc.). Existent collaborations will be utilized and additional collaborators with appropriate skills in stem cell research, regulatory affairs and GLP/GMP have expressed willingness to collaborate/participate.