Executive Summary The principal investigator (PI) proposes to use stem cell techniques to develop a therapeutic strategy for pulmonary vascular disease, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). These conditions lead to right heart failure and death, usually within 5 years of diagnosis and affect ~100,000 patients / year. Currently, there is no cure for these diseases. The PI proposes to isolate and study cells obtained from the pulmonary artery (PA) of patients undergoing endarterectomy to determine whether misguided endothelial and mesenchymal progenitor cells are responsible for the pathogenesis of these diseases, and to develop a cellular model of PAH using reprogrammed induced pluripotent stem (iPS) cells from patients’ diseased tissue. Using these cells, they intend to search for small molecules that alleviate abnormal proliferation and believe these observations will lead to a clinical trial. Although the PI presents an interesting concept, and the significance underlying this project is high, the disease target is questionable and unlikely to lead to a clinical trial in the next 5 years. The work proposed is somewhat premature, speculative and unfocused. While it could potentially lead to interesting and important discoveries about the pathogenesis of pulmonary vascular disease, one reviewer felt that it is unlikely that isolated and reprogrammed pulmonary fibroblasts will contribute to our knowledge of how this disease develops, since pulmonary vascular diseases are systemic diseases with specific phenotypes that are probably difficult to recapitulate with cells cultured in vitro. Furthermore, the reviewers agreed that the scientific readiness and maturity of the proposed project is limited. The hope that small molecules inhibiting proliferation of aberrant vascular cells could be developed for initial clinical trials as a result of this work is not supported by the status of the field at the present time. Furthermore, a strategy for drug screening, testing of individual substances, and selection of endpoints was not described in the proposal, and it was difficult for reviewers to determine whether the proposed strategy would be effective. The PI is of excellent caliber, s/he is a productive and successful investigator with a strong background in basic science in the area of pulmonary hypertension and in clinical trials. S/he is an MD, PhD and a professor of medicine and vice chair for research in a department of medicine at the home institution, which provides an excellent environment. S/he is also a fellow of the American Academy for the Advancement of Science. S/he has a good track record in leadership, but hasn’t demonstrated expertise in leading disease-focused, multidisciplinary teams in the past. The PI seems to be building a good team of investigators composed of clinicians and researchers. However, the PI proposes to reprogram somatic cells from patients by over-expressing the pluripotency genes in the patients’ vasculopathy cells, but there is no evidence of expertise in iPS cell technology within the team, and the PI assumes that this will be done easily. The reviewers agreed that the planning process is not well delineated in the proposal, and commented that it lacks focus as well as milestones. An outline of the organization was listed, but the focus of the team and the role of each investigator was not clearly explained. Reviewer Synopsis The investigators propose to establish a disease team to study the role of stem cell therapy in pulmonary vascular disease, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). These conditions lead to right heart failure and death, usually within 5 years of diagnosis and affect ~100,000 patients/year. Although these diseases occur in varied clinical settings, affected patients have been shown to have abnormal pulmonary vascular remodeling. The investigators propose to isolate and study cells obtained from the pulmonary artery (PA) of patients undergoing endarterectomy to determine whether misguided endothelial and mesenchymal progenitor cells are responsible for the pathogenesis of these diseases. They will also study the microenvironment and will search for small molecules that alleviate abnormal proliferation. They believe these observations will lead to a clinical trial. Reviewer One Comments Concept: The target is questionable and unlikely to lead to a clinical trial in the next 5 years. The work proposed is somewhat premature, speculative and unfocused. While the work could potentially lead to interesting and potentially important discoveries about the pathogenesis of pulmonary vascular disease, there is little evidence that these observations, if confirmed, would readily lead to the development of a clinical trial. The hope that small molecules inhibiting proliferation of aberrant vascular cells could be developed for initial clinical trials as a result of this work is not supported by the status of the field at the present time. Principal Investigator: The PI, Dr. Jason Yuan, is an MD, PhD and a professor of medicine and vice chair for research in the department of medicine at UCSD. He is also a fellow of the American Academy for the Advancement of Science. He has a strong basic science background in the area of pulmonary hypertension. He has the training and scientific background to lead this team, but hasn’t demonstrated a track record in leading disease-focused, multidisciplinary teams in the past. Planning Approach: The planning process was not well delineated. An outline of the organization was listed, but the focus of the team and role of each investigator wasn’t clearly explained. Reviewer Two Comments Concept: Pulmonary vascular disease, such as pulmonary hypertension, is a devastating and fatal condition that leads to heart failure. Currently, there is no cure for the disease. The goal of the proposal is to organize a team to develop a novel stem cell based therapeutic strategy for pulmonary hypertension using stem cells derived from patients’ diseased tissues. The team will be composed of clinicians and researchers. Thus, the rationale and significance underlying this project is high. The scientific readiness and maturity of the basic knowledge necessary for the successful accomplishment of the goals is, however, limiting. Principal Investigator: The principal investigator is of excellent caliber and the UCSD environment is among the best in California. Planning Approach: The plan of attack is unfortunately very poorly described and lacks focus as well as milestones. For example, the PI proposes the use reprogrammed somatic cells from patients (iPS) by over-expressing the pluripotency genes in the patients’ vasculopathy cells, but there is no evidence of expertise in this bourgeoning technology within the team, and the PI assumes that it will be done easily. Also, characterization of compounds that can regulate vascularization using this system, and having it ready for clinical trials within five years seems at best unrealistic, if not naive. Reviewer Three Comments Concept: - interesting concept and disease (PAH); problem however that it is unlikely that isolated and reprogrammed pulmonary fibroblasts will contribute to our knowledge of how this disease develops; systemic disease, with specific phenotype that is likely to be difficult to recapitulate in vitro with cells - also difficult to understand how the drug screening will be carried out, what the endpoints are and how effective this strategy will be - missing link to clinical trial, how the individual substances will be tested and how this will translate into a clinical trial within the next 5 years - seems to build a good team of investigators, however the overall goal is questionable Principal Investigator: - productive and successful investigator with good track record in leadership - excellent environment with expertise in PAH and clinical trial Planning Approach: - approach not clear to the reviewer