Early Translational II
Acute Lung Injury is a serious complication of several clinical disorders including severe pneumonia and other infections. The mechanism for development of this syndrome includes damage to the lung air and blood barriers resulting in accumulation of fluid within the lungs – so called “drowning on the ground”. Patients cannot absorb sufficient oxygen from air, which can lead to respiratory failure and death. There is a major pressing medical need for a new treatment of patients with Acute Lung Injury, a syndrome that has a high mortality rate (40%) and affects 200,000 patients annually in the US. Currently, the only treatment is supportive care with lung protective mechanical ventilation. There is compelling experimental and preclinical evidence that adult human mesenchymal stem cells and their secreted products have a high likelihood of being effective in the treatment of Acute Lung Injury in humans. The studies that we propose in this application will advance the field of intensive care medicine and treatment of severely ill patients. The objective of the proposed research is to develop a Target Product for Therapy of Acute Lung Injury based upon the concept that the human stem cells produce large quantities of biologically active substances with therapeutic potential. Balanced array of biologically active substances from stem cells facilitates regeneration of injured tissue. Compared to adult human stem cells from the bone marrow which are mostly used currently, human placental cells possess higher therapeutic potential for treatment because of their more primitive nature, higher activity, better growth characteristics, cost and availability. We will demonstrate the potential of placental stem cells and their products to facilitate repair of injured lung. We will characterize the composition of biologically active substances in products of placental stem cells. First, we will investigate importance of multiple major growth factors and anti-inflammatory proteins in the mechanisms of action by gene silencing. Second, we will determine the effects of specific or non-specific cell stimulation on release of biologically active substances by cells to determine ways to facilitate these effects. We will develop a therapeutic product and demonstrate its effectiveness when delivered to the lungs as an aerosol. Use of cell products instead of live stem cells allows easier production and delivery, standard development, excludes tumor development and adverse immune reactions. The Target Product will be tested in animals and human lungs.
Statement of Benefit to California:
Stem cell-based therapies are the promising future of medicine. The application of this treatment is limited because of the restricted supply of effective and appropriate stem cell lines, as it is necessary to match certain characteristics of the donor’s and host’s immune systems. Acute Lung Injury affects approximately 20,000-30,000 California residents, and 40% of these patients do not survive. Our pioneering studies demonstrated that human placenta may be used as a source of mesenchymal stem cell lines for the treatment of ALI. These cell lines derived from human placenta will contribute to clinical applications. Our hypothesis is that the tissue of human term placenta is a high capacity source of primitive stem cells capable of improving outcomes in patients with ALI. Other diseases that can potentially be cured by the use of stem cell treatment afflict significant number of individuals in California. These stem cell lines will be used in regenerative medicine research and cell replacement therapies as well as the development of new treatment approaches. The enhanced and extended lives of the individuals will represent an evident benefit; the savings to the health care system as a consequence of their cure will straightforwardly benefit all California taxpayers. Ultimately the knowledge and experience produced by the work proposed will contribute to the goal of making stem cell transplantation and new medical approaches available to a much broader group of patients, thus greatly extending the benefits to the affected individuals and to the taxpayers of California.
The goal of this Developmental Candidate Feasibility (DCF) application is to develop a therapeutic product for the treatment of Acute Lung Injury (ALI). This product would not include stem cells but, instead, would be composed of growth factors, cytokines, hormones, and RNA/DNA containing microvesicles secreted from placental-derived mesenchymal stem cells (MSCs). The approach is based on the applicant’s previous demonstration that secreted products of bone MSCs showed effectiveness in treating ALI in a perfused lung model. The proposal addresses three aims: 1) to use animal models of lung injury and a human ex-vivo perfused lung preparation to test the potential of multipotent placental MSCs and their products to facilitate repair following ALI; 2) to characterize the composition of growth factors, cytokines and exosomes in products of placental stem cells; 3) to demonstrate the potency of products of placental stromal cells in the treatment of ALI. The reviewers agreed that the objective of this proposal was reasonable and if successful, the proposed therapy would address an unmet medical need in the treatment of ALI. However, reviewers had serious reservations about the rationale for the proposed approach. In particular, it was unclear why conditioned media and a variety of secreted components would be evaluated, since the applicant had previously demonstrated that most of the protective effects were due to a single, identified growth factor. Reviewers also questioned the proposed route of product administration and viewed other translational components of the project as premature, requiring substantial basic research before translation activities would be appropriate. Although reviewers appreciated the substantial preliminary data, they voiced significant concerns about the feasibility of the proposed research. They found the research plan vague and lacking in critical details of methodology and interpretation of results. For example, it was unclear how particular experiments would inform the choice of components for the eventual developmental candidate. Reviewer enthusiasm was further diminished by inadequate discussion of potential pitfalls, the lack of alternate plans, vague milestones, and lack of clear, quantifiable endpoints. Reviewers praised the research team’s expertise and described the investigators as leaders in the ALI field and well suited to carry out the proposed research plan. The reviewers noted that the Principal Investigator (PI) has coordinated several clinical trials for new candidates to treat ALI and has published relevant papers on MSCs in the lung. The institutional support and environment were judged to be of excellent quality. Reviewers expressed minor concerns about the apparent lack of coordination or a formal communication plan among the team members. In summary, this application describes a DCF that proposes a strategy to evaluate the protective effect of conditioned media obtained from placental-derived MSCs to treat ALI. Strengths of the proposal included its focus on an important unmet medical need and the experience of the applicant and research team in the ALI field. Weaknesses included a number of significant problems with the rationale and experimental plan, greatly lowering reviewers’ enthusiasm for the feasibility of the proposed research.