Bone-marrow derived mesenchymal stem cell based therapy for severe bacterial pneumonia and septic shock
New Faculty Physician Scientist
This proposal is focused on developing bone marrow derived mesenchymal stem cells (MSCs) as a therapy for critically ill patients who have severe pneumonia leading to lung injury and an overwhelming bloodstream infection (sepsis). This syndrome is the most common cause of death among patients in Intensive Care Units, and it carries a mortality rate of 40-50% despite the best supportive care and accounts for over 200,000 deaths/year. New therapies are urgently needed. MSCs are adult stem cells usually obtained from the bone marrow that have been demonstrated to have significant protective effects in experimental models of severe lung injury and sepsis. MSCs work by reducing excessive inflammation, promoting the clearance of bacteria, and facilitating the repair of injured organ tissues. The studies in this proposal will use validated, clinical grade MSCs in a mouse model of severe lung injury and sepsis to help answer important remaining questions in the effort to develop MSCs a therapy for critically ill patients. Specifically, it will determine the optimal growth conditions for MSCs, the optimal manner in which MSCs should be delivered to patients, and whether purified proteins obtained from MSCs can achieve protection similar to using live cells. The results from these experiments will significantly enhance our ability to develop the most optimal MSC based therapy for patients with severe lung injury and sepsis that can be tested in a clinical trial.
Statement of Benefit to California:
Public Health Benefit. The proposed research aims to develop a novel, stem cell based therapy for critically ill patients who have severe lung injury and sepsis from bacterial pneumonia. This is the most common cause of death among critically ill patients with a mortality rate of 40-50% despite the best, current supportive care. The incidence and severity of this syndrome is expected to increase as the population of California and the nation increases. Furthermore, antibiotic resistance has significantly hampered the treatment of patients with this clinical disease, and the need for new forms of therapy is high. Therefore, this proposal will provide significant potential benefit to the citizens of California by helping to treat this important public health problem. Economic Benefit. During the current economic climate in California and the nation, the impact that an investment such as the current CIRM program has on improving the employment potential of Californians is important to consider. As part of this proposal, new personnel will be hired to help in the completion of the studies. These individuals, along with the principal investigator, will become part of a highly trained group of investigators that will help create a sustainable program of innovative stem cell research for patients in California who have lung disease.
Executive Summary The overall objective of this proposal is to develop bone marrow derived mesenchymal stem cells (MSCs) as therapy for patients with severe sepsis and lung injury due to bacterial pneumonia. Despite several attempts there have been no pharmacological agents that have consistently reduced mortality from severe sepsis. Three aims have been proposed to achieve the objectives of the proposal. In Aim 1 the applicant plans to identify optimal growth conditions for MSC expansion. In Aim 2 the applicant will use an established mouse model of gram-negative pneumonia and septic shock to identify the optimum route, dose and timing of cell delivery. Finally, in Aim 3 the applicant will explore whether purified paracrine factors secreted by MSCs are as effective in promoting lung repair as MSCs themselves. Research Plan - The research is minimally innovative as it is based on similar studies carried out previously by the applicant and the concept of using MSCs to treat this indication is well-established. - Reviewers questioned the reliance of the experimental approach where the cells are provided by an industrial collaborator whose reputation is not well established. - The reviewers questioned the experimental design of the project. For example there was a concern on the timing of the delivery of therapeutic cells in the mouse model relative to what is seen clinically, and the fact that the chosen model doesn’t replicate the pathophysiology of the disease. - Reviewers commented on lack of experimental details on the study of paracrine factors for therapeutic benefit. For example it was unclear which paracrine factors will be administered and at what dose, and whether they would be given alone or in combination. Without this information it was difficult to judge the feasibility of the project. - Reviewers were not convinced that the proposed preclinical studies could be utilized as IND-enabling studies and questioned the relevance and scalability of the mouse model when considering optimum doses, timing and mode of administration to human. In addition, IND-enabling work should assess efficacy in combination with current standard of care therapies. - Reviewers thought that the applicant had underestimated the immunogenicity potential of MSC, especially in the xenogeneic setting and the intravenous (i.v.) route of delivery. - There was not enough work proposed in the application to justify the proposed time or budget. Principal Investigator (PI) - The PI is a practicing Pulmonologist and Critical Care physician with MSC research background. - The reviewers did not find PI’s publication record to be impressive and were concerned about the lack of productivity. - The proposed mentors have good qualifications in mentoring successful physician-scientists. Institutional Commitment - The applicant institution has made a commitment to the candidate's translational research career, providing laboratory space, salary, research support and mentoring. There is excellent collaborative potential within the environment and immediate area. - The applicant institution has an excellent track record in development of physician scientists, and a strong commitment to researchers and clinicians in the area of stem cell research. Responsiveness - The proposal was considered to be highly responsive and unlikely to get funding from traditional funding agency due to exploratory nature of the research.