Funding opportunities

{REDACTED} Cardiovascular Regenerative Team

Funding Type: 
Disease Team Planning
Grant Number: 
DT1-00710
Principle Investigator: 
Institution: 
Funds requested: 
$55 000
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
Heart failure affects 5 million patients in the U.S., representing the most common cause of hospital admission and resulting in 300,000 deaths annually. Despite aggressive treatment with advanced pharmacotherapies and implantable devices, the 5-year survival is only 50%. Cardiac transplantation is limited to 2,000 patients per year due to the lack of suitable donors. Therefore, a strong mandate exists for novel strategies to treat patients with end-stage heart failure. Recent investigations support cell therapy as a rational strategy to restore and regenerate the injured myocardium. However, clinical studies suggest that adult stem cell therapy provides only limited efficacy. The {REDACTED} Cardiovascular program has a distinguished history that includes several firsts in transplantation and implantation: the first human heart and heart-lung transplants in the US and first human endovascular stent-graft for aortic aneurysm. The {REDACTED} Cardiovascular Regenerative Team follows this tradition of translational research to focus on efficient, integrated collaboration across multiple disciplines within {REDACTED} and to accelerate clinical implementation of innovative ideas by fostering partnership between academia and industry. For the CIRM Disease Team grant, the {REDACTED} proposes to directly test the utility of human embryonic stem cell (hESC)-based therapy for significant and sustained functional restoration of injured myocardium. Our approach is grounded in fundamental investigations performed by the team members. We propose a collaborative strategy based on novel discoveries in our laboratories that will culminate in the first Phase I safety trial of transplantation of hESC-derived cardiovascular stem cells for patients with end-stage heart failure. The specific aims are: 1) Derive clinical-grade hESCs using good manufacturing practice (GMP). 2) Differentiate, purify and characterize mesodermal cells for cardiovascular regeneration. 3) Deliver and monitor hESCs in large animal model. 4) Transplant GMP-hESC derived progenitor cells into the failing heart of patients awaiting heart transplantation. The planning effort of {REDACTED} will merge innovative approaches in human stem cell biology with the highest standards in clinical safety to address a fundamental yet very critical issue in translational research: safety of GMP-hESC derived progenitor cells in the patients with failing heart.
Statement of Benefit to California: 
Coronary artery disease continues to be the leading cause of death in the United States. Recent advances in cardiovascular therapy have improved immediate survival following an acute myocardial infarction (heart attack or arrest). The persistence of high overall mortality of coronary artery disease despite improved treatment is due to a shift in the disease process. Studies have demonstrated a critical role of the infarcted myocardium in the development of congestive heart failure (a common form of progressive heart failure). Indeed, the incidence of congestive heart failure is now reaching epidemic proportions. Today, there are more deaths from patients developing congestive heart failure than those sustaining acute myocardial infarction. Congestive heart failure is the leading cause of hospital admissions resulting in approximately 300,000 deaths annually. There are nearly 5 million Americans who are suffering from this illness with 550,000 new cases reported each year. Over the last several decades, advances in biomedical technology provided significant improvement in morbidity and mortality. Unfortunately, however, the average 5-year survival today still remains around a dismal 50%, creating a major public health concern. Heart transplantation is an established treatment for end-stage congestive heart failure. Yet, this definitive therapy is limited to only 2000 donor hearts per year. Thus, a strong mandate exists for an alternative therapeutic option. Human embryonic stem cells (hESC) have demonstrated the ability to differentiate into cardiac cells, representing a potential application of cell therapy to restore the injured myocardium. It is notable that the public health impact of congestive heart failure in California is representative of the emerging epidemic seen across the United States. As the most populous State in the nation, congestive heart failure has resulted in an equivalent health care burden to California citizens in terms of financial cost, morbidity and mortality. The State of California stands to benefit tremendously with scientifically proven safe and definitive therapy for congestive heart failure using hESC.
Review Summary: 
Executive Summary The intent of this proposal is to develop a plan that will bring about a Phase I safety trial of transplantation of human embryonic stem cell (hESC)-derived cardiovascular stem cells for patients with end-stage congestive heart failure (CHF). The planning effort will include derivation, differentiation (under GMP conditions) and characterization of hESC-derived progenitor cells. Cells will be delivered in a porcine myocardial injury model, to monitor engraftment and assess procedural safety. Finally, GMP-hESC derived progenitor cells will be transplanted into the failing hearts of patients undergoing left-ventricular assist device (LVAD) implantation as a bridge to transplant. Explanted hearts will undergo histological and molecular analyses of cell engraftment, differentiation, and teratoma formation. The planning effort will converge these approaches and determine safety of GMP-hESC derived progenitors. Reviewers concurred that the research concept is focused on a significant clinical problem, and that existing therapies for end-stage cardiac failure (LVAD implantation and transplantation) carry not only major emotional and fiscal costs but are limited by the supply of hearts and by issues related to rejection. As such, novel means of therapy are needed and stem cells offer the hope of a superior alternative approach. There is a good deal of evidence in the literature from this and other groups that at least some stem cell therapies are safe in this clinical context. Although effectiveness has been minimal to modest at best, the field is young. Reviewers felt that the components of this plan are well described and the experiments could be performed once appropriate cell populations of GMP quality are obtainable. This could be achieved within the 5 year timeframe of the CIRM RFA guidelines. Several strengths of this concept included a focus on cardiomyocyte progenitor cells, testing in a large animal model, performing the appropriate imaging studies and then going into a safety and feasibility trial in 5 years. Furthermore, the pathologic analysis of the explanted hearts will facilitate analysis of the functional outcomes with histologic/molecular studies. One reviewer commented that the choice of patients is clinically astute and ethically impeccable. In summary, although the proposed concept is highly ambitious, if everything breaks right along the way, this goal will be attainable. Reviewers agreed that the PI is well qualified to lead this multidisciplinary effort, and is a strength of this proposal. The PI is Professor and Chair of Cardiothoracic Surgery and has an admirable track record of accomplishments relevant to the proposal, including an exemplary background in transplantation, and robust collaborations on cell therapy both within the applicant institution and more widely. The assembled team members are equally recognized in their areas of expertise. The PI has the expertise to direct the technical aspects of the proposal and the stature and leadership to assemble and direct the multidisciplinary cardiac team. A major strength of this application is the level of organization already achieved going into the planning process. This includes identifying the basic and clinical scientists, the molecular diagnostics team, a promising group of young investigators and industry and academic partnerships. Reviewers felt the planning approach was highly organized and collaborative. The proposed multidisciplinary team is an appropriate unit to push ahead with the more detailed planning of the approaches to be employed and executed. Respected senior scientists head each of the “Aim groups” and are capably supported by promising junior individuals, and the design presented for the planning phase instills confidence that the aims will be carried out. The collaborative nature of the group is clearly evident. Moreover, linkages have already been established with partners in industry, arrangements have been made with regard to a GMP facility and a plan has been enacted for obtaining FDA approval. As such, this team should be able to position itself in highly competitive fashion for the proposed Disease Team Research Awards. Reviewer Synopsis Intent: Bring about a Phase I safety trial of transplantation of hESC-derived cardiovascular stem cells for patients with end-stage CHF. Aims: 1) hESCs derived, cultured and maintained under GMP conditions. Genomic, proteomic and toxicological analyses of cell lines performed, alternative approaches using patient-specific reprogrammed stem cells investigated. 2) GMP-hESCs will be differentiated into mesodermal cells, enriched for cardiac and endothelial progenitors and characterized by molecular and functional assays. 3) Deliver hESCs in a porcine myocardial injury model, monitor engraftment and assess procedural safety. 4) Transplant GMP-hESC derived progenitor cells into failing hearts of patients undergoing LVAD implantation as bridge to transplant. Explanted hearts will undergo histological and molecular analyses of cell engraftment, differentiation, and teratoma formation. The planning effort will converge these approaches and determine safety of GMP-hESC derived progenitors. Reviewer One Comments Concept: This proposal represents an approach to functional restoration of injured myocardium by the Stanford Cardiovascular Regenerative Team (SCRT). The ultimate goal is to use hES cell derivatives to treat cardiac injury. The underlying hypothesis is that adult stem cell therapy (at least to date) provides only limited efficacy. The components of this plan are well described and the experiments could be performed once appropriate cell populations of GMP quality are obtainable. This could be achieved within the 5 year timeframe of the CIRM. Principal Investigator: The PI is accomplished Professor of Cardiothoracic Surgery who has already contributed to the stem cell field in collaboration with Irv Weissman and associates. He has the expertise to direct the technical aspects of the proposal and the stature and leadership to assemble and direct the SCRT. Planning Approach: The SCRT is an appropriate unit to push ahead with the more detailed planning of the approaches to be employed and executed. The SCRT includes all the requisite components including basic and clinical scientists, junior investigators, and industrial partners (for cell preparation and quality control). Reviewer Two Comments Concept: The problem of heart failure is indeed a critical one in the US, and existing therapies for end-stage failure (LVADs and transplantation) carry not only major emotional and fiscal costs but are limited by the supply of hearts and by issues related to rejection. As such, novel means of therapy are needed and stem cells offer the hope of a superior alternative approach. There is a good deal of evidence in the literature from this and other groups that at least some stem cell therapies are safe here. Although effectiveness has been minimal to modest at best, the field is yet young. The approach here, bringing a highly skilled team together to test hESC-derived cells is clearly presented in a sequence that runs from learning more about the cell biology to obtaining GMP cells and after appropriate studies involving genomics/proteomics and systems biology, testing in a large animal model, doing the appropriate imaging studies and then going into a safety and feasibility trial in 5 years. Although highly ambitious, if everything breaks right along the way, this goal will be attainable. Principal Investigator: The PI has an outstanding record of leadership in this field and the team members he has assembled are equally recognized in their areas of expertise. Indeed a major strength of this application is the level of organization already achieved going into the planning process. This includes identifying the basic and clinical scientists, the molecular diagnostics team, a promising group of young investigators and industry and academic partnerships. Planning Approach: Respected senior scientists head each of the “Aim groups” and are capably supported by promising junior individuals. The collaborative nature of the group is clearly evident. The design presented for the planning phase is sufficient to instill confidence that the aims will be carried out. Moreover, linkages have already been established with partners in industry, arrangements have been made with regard to a GMP facility and a plan has been enacted for obtaining FDA approval. As such, this team should be able to position itself in highly competitive fashion for the proposed Disease Team Research Awards. Reviewer Three Comments Concept: The application is solidly focused on the goal of GMP-grade hESC-derived cardiomyocytes as treatment for end-stage heart failure. By comparison to less competitive applications, the proposal is tightly cohesive, well-organized, describes a systematic approach to the many R&D tasks that must each be optimized, and is founded upon a well-posed clinical target for which no adequate alternative exists. The choice of patients undergoing implantation of a mechanical LV assist pump as a temporizing bridge while awaiting transplantation is clinically astute and ethically impeccable. The applicants have made particular effort, in the choice of partners and hESC platforms, to maximize the likelihood of reaching first-in-human studies with a cogent timetable. Principal Investigator: Robert Robbins is Professor and Chair of Cardiothoracic Surgery at Stanford. He has an admirable track record of accomplishments relevant to the proposal, including an exemplary background in transplantation, and robust collaborations on cell therapy both within Stanford and more widely. His leadership value is seen as very strong and one of the assets of the grant. A weakness worth noting is the PI’s apparent lack of current NIH peer-reviewed support. However, this does not severely affect the reviewer’s enthusiasm, as reflected in the outstanding overall score. Planning Approach: The team is stellar in all respects. There is enviable depth, ranging from the most basic aspects of directed differentiation to the applied aspects of GMP production (for which an experienced commercial partner is engaged, and highly auspicious cells from the Karolinska are proposed as the basis) and large-mammal models. The PI has proven capacity to orchestrate teams that operate cohesively and fruitfully. Another particular strength is the depth of imaging research at Stanford.
Conflicts: 

© 2013 California Institute for Regenerative Medicine