Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology, characterized by excessive scarring (fibrosis) of the lung due to an increase in number and uncontrolled activity of cells called fibroblasts. Destruction of normal lung structure usually leads to death from lung failure within five years of diagnosis. Currently available therapeutic approaches offer little clinical benefit. It has recently been suggested that injury to the lining cells of the lung (epithelial cells) may contribute by releasing substances (mediators) that stimulate fibroblasts to increase in number leading to scarring. In turn, fibroblasts may release mediators that can lead to epithelial cell death preventing normal repair.
Studies in animals have demonstrated that administration of a particular type of stem cell derived from adult bone marrow known as a mesenchymal stem cell (MSC) can improve outcome from a number of types of lung injury and prevent subsequent scarring. The mechanisms responsible for the helpful effects of MSC are not well understood and may include changes in the immune system and secretion of mediators that prevent epithelial cells from dying. This may tip the balance in favor of repair of lung damage and resolution of the injury. Experimental studies as well as clinical trials of MSC in several non-pulmonary diseases have already shown beneficial effects. Given that MSC appear to be the most immediate available opportunity for stem cell-based therapy of lung disease, the overall goal of this proposal is to assemble a Disease Team to plan a proposal for use of MSC as a therapeutic tool for IPF.
A team will be assembled with expertise in several areas including expertise in growing MSC and animal models of lung injury, preparation of products of sufficiently good quality for administration to humans, obtaining approval of new products through the Food and Drug Administration and clinical trials in patients. In initial meetings, members of the team will assess whether any other specific expertise is required. Once assembled, team members will participate in regular meetings and conference calls to plan and prepare the research proposal for development of the research proposal. The PI will actively manage the team, using deadlines for specific objectives, including development of protocols, assignment of writing tasks and coordination of written materials.
Development of MSC for treatment of IPF is ideally suited to a team approach. The varying types of expertise required for this project are usually not found at a single institution and few investigators have both knowledge of basic stem cell biology and the ability to translate findings into clinical trials. The Disease Team approach will bring together individuals of varying expertise who might not otherwise have interacted to develop a proposal for translation of MSC to the clinic for lung disease, which responds directly to the objectives of this award.
Statement of Benefit to California:
Chronic lung disease is the 4th leading cause of death among Californians and causes an untold amount of suffering and disability. Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disease of unknown cause that causes progressive scarring (fibrosis) of the lung and usually results in death within 5 years of diagnosis. IPF, along with other types of fibrotic lung diseases, is believed to be caused by an initial lung injury followed by inadequate or abnormal repair. Medication alone has not been helpful in slowing disease progression, so there is a need to develop new approaches, such as cell-based therapies. In animal experiments, mice with lung fibrosis that had been given bone marrow-derived mesenchymal stem cells (MSC) intravenously had less severe lung disease. Although scientists initially thought that MSC would improve lung function by replacing fibrotic lung tissue with normal lung cells, very few MSC were found to have engrafted in the injured lung as actual lung cells. The decrease in lung fibrosis in MSC-treated animals is likely due to other mechanisms, such as modifying the immune response or by producing tissue components that set the stage for the lung cells themselves to participate in normal repair processes. These and other experiments have led to studies in humans with a variety of non-lung diseases such as severe immunologic, cardiovascular and neurologic disorders in which MSC have been shown to be both safe and of benefit. MSC are readily procured from aspiration of adult bone marrow and are able to be expanded in cell culture. However, there has been little work in using MSC for the treatment of fibrotic lung diseases. In developing a proposal to treat patients with IPF with MSC, we will be exploiting the expertise in California of basic scientists with knowledge of stem cells and lung cell biology and clinical investigators who will be able translate the basic science to treatment of patients. This approach is the most mature opportunity currently available for the treatment of severe fibrotic lung disease. A study such as this puts California at the forefront in the development of novel treatments for lung diseases and accelerates the advancement of novel cell-based therapies. Although commercial sources of MSC have been developed for use in clinical trials, development of well-characterized clinical grade MSC could serve as a resource for CIRM investigators throughout California with application to other diseases. This could have an additional benefit to California, by attracting both researchers and biomedical investors to the state. Should effective treatments for advanced lung diseases be developed as a result of this research, productivity and longevity of all Californians should be positively impacted by this work.