Development of Novel Therapeutic Strategies for Pulmonary Vascular Disease Using Stem Cells Derived From Patients' Diseased Arterial Tissues
Disease Team Planning
High blood pressure in the lungs, which is more commonly referred to as pulmonary hypertension, is a major pulmonary vascular disease. Pulmonary hypertension occurs when blood has difficulty flowing smoothly through the blood vessels or arteries in the lungs. It may occur with no specific medical reason or it can arise as a major side effect of many other diseases including heart disease, HIV/AIDS, and liver disease. Pulmonary hypertension can cause specific and significant changes in how the pulmonary blood vessels (the 'tubes' that conduct the blood within the lungs) contract and allow blood to flow. Pulmonary hypertension is both a progressive and fatal disease, with over 25,000 new patients diagnosed each year in the US alone, the greatest proportion being young women. One of the main causes of pulmonary hypertension is the increased resistance to blood flow because the pulmonary blood vessel wall becomes thickened; as a result, the heart must work much harder to pump out enough oxygen-filled blood to satisfy the body's demands. If untreated, this causes heart failure and death. The walls of pulmonary blood vessels are composed of different types of cells, some of which are muscular (called smooth muscle cells) and cause arteries to contract and pump blood through. A single layer of cells lining the wall of the arteries (called endothelial cells) acts like a filter and prevent material from penetrating into the arteries where they might cause contraction or change how other cells work. Both of these cell types start off as tissue specific stem cells. These stem cells can transform themselves into other types of cells in the body depending on the stimulus or conditions within the body. We believe that, in pulmonary hypertension, some of these stem cells have become misguided and are constantly evolving into other cell types, causing narrowing of the lung blood vessels due to contraction or thickening of the wall. The ultimate goal of this project is to use stem cells as a tool to develop new treatments for pulmonary hypertension. For this to happen, we propose to do the following: 1. To isolate specific stem cells from patients' diseased lung tissues and to examine different cellular mechanisms which we believe are involved in the development of pulmonary hypertension. 2. To find a way of targeting the "misguided" stem cells from patients to prevent them from changing into abnormal cell types and cause sustained contraction and pulmonary arterial wall thickening. 3. To use these tissue specific stem cells to develop new chemicals or molecules which could be used in patients. 4. To conduct Phase-I clinical trials in patients with pulmonary hypertension using the new drugs developed from the stem cell studies.
Statement of Benefit to California:
According to the Centers for Disease Control and Prevention, there were 260,000 hospitalizations nationwide in 2002 for Americans with pulmonary hypertension (high blood pressure in the lungs); 15,668 deaths listed pulmonary hypertension as a complication in the US. In California, the number of Medicare hospitalizations alone due to pulmonary hypertension was 27,390 in 2000-2002, and more than 4,300 people died due to pulmonary hypertension. Women are diagnosed and/or hospitalized for pulmonary hypertension at almost double the rate of men. People with pulmonary hypertension are unaware of the condition until it is well established when they experience shortness of breath with minimal activity, fatigue, chest pain, dizziness, and fainting spells. Patients generally have a normal regular “systemic” blood pressure, but the blood pressure in their lungs (“pulmonary arterial pressure”) is elevated because arteries in the lungs are narrowed due to contraction or blockage. Pulmonary hypertension is fatal, eventually causing heart failure. There are several forms of pulmonary hypertension, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Idiopathic PAH, by definition, has no known cause at present, although its occurrence has been linked to some genetic mutations and to the use of appetite suppressants (“diet drugs”). We estimate that ~100,000 Americans have idiopathic PAH, with ~300 new cases diagnosed annually; the greatest numbers are reported in 20-40 year old women. It also affects people of all races and cultural groups equally. Survival after diagnosis is < 3 years. There is no cure for idiopathic PAH, although some drugs may slow disease progression and improve patients’ exercise capability. CTEPH is more common, with ~25,000 new cases reported each year. CTEPH patients represent a mere 4% of the total people diagnosed with pulmonary embolism (i.e., blood clots in the pulmonary blood vessels). Pulmonary vascular clots can be removed surgically; however, >35% of the patients still have pulmonary hypertension after surgery and need to receive drug therapies as for PAH patients. Californians account for more than 12% of the national population, with great racial and ethnic diversity. Based on the statistics nationwide, there would be more than 10,000 PAH patients in California. Each year, there would be more than 3,000 Californians suffering from CTEPH. There is no cure for pulmonary hypertension (regardless of the form), although surgery can help in cases like CTEPH. Medication can improve exercise capability and delay pulmonary hypertension-related death. However, most of the drugs clinically used to treat pulmonary hypertension are very expensive (e.g., $100,000-$250,000 per year for epoprostenol). The goal of this project is to use stem cells derived from patients’ diseased lung tissues as an experimental model to develop new therapeutic approaches for pulmonary hypertension.
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