Disease Team Planning
Over 5 million Americans suffer with congestive heart failure, and 500,000 new cases are diagnosed each year. Unfortunately, these numbers are likely to worsen over the next two decades, as the total number of heart failure patients is expected to rise by over 50%. Ischemic heart disease is the most common cause of heart failure, and stem cell transplantation may represent the first realistic clinical strategy for actually reversing the deleterious effects of what has been considered irreversible damage to the heart resulting from myocardial infarction. However, significant hurdles must still be overcome before successful human translation of this strategy can be realized; in particular, a means is needed both for preventing the rapid death of most of the transplanted cells and for encouraging their functional contribution to the heart. We propose a strategy, termed Matrix-Assisted Myocardium Stabilization (MAMS) that has been developed by a collaboration of bioengineers, stem cell biologists, and cardiac surgeons to improve the efficacy of stem cell transplantation into a heart injured by MI. The goal of our research proposal is to enhance the survival and performance of cells transplanted into ischemically damaged heart muscle and that, within a four-year period, can begin clinical testing for preservation of cardiac function and prevention of post-MI heart failure.
Statement of Benefit to California:
The proposed research will benefit California by preserving and strengthening California’s position as a leader in the emerging field of human stem cell therapeutics. Through the recent passage of Proposition 71, the voters of California have identified stem cell research as a key area of focus for the state, with anticipated positive impacts including: creation of biotechnology jobs, attraction of leading researchers to Californian universities, creation of valuable intellectual property, and advancement of therapeutics beneficial to California’s residents. This proposal will bring California’s diverse technical resources to bear towards this goal by combining the expertise of leading academics in the fields of biomaterials and bioengineering with world-leading clinicians to the field of human stem cell therapeutics. Millions of Californians stand to benefit from development of stem cell-based therapies in our program of heart failure treatment, many more could be affected by the translation of our technology to similar therapies for additional cardiac degenerative disorders.
Executive Summary The proposal is focused on a therapeutic approach to prevent congestive heart failure (CHF) following heart attack. The therapy is directed at limiting myocardial remodeling, a key component of CHF, that results from acute myocardial infarction. The applicant proposes a tandem stem cell and biomaterials-based approach in which stem cells within a pro-survival matrix will be injected into the heart, leading to a stabilization of the myocardium in the infarct region. This stabilization is predicted to prevent CHF progression. This proposal seeks to address a disease target of high incidence and importance. An innovative and novel approach is outlined which could provide substantial patient benefit. However, reviewers felt that the proposed concept was premature and that a substantial amount of basic research is needed before the approach could move toward clinical application. In particular, development of the proposed therapy will require identification and analysis of pro-survival biomaterials, production and characterization of appropriate stem cell populations, optimization of cell encapsulation and cell-matrix stabilization methods, and analysis with animal models, along with other important unresolved issues. Prospects for clinic trials within five years appear low. The PI is an expert in biomaterials science and bioengineering. He/she has a substantial record of publication and collaboration and has extensive experience in translational research. The PI is well qualified to direct the proposed, multi-investigator project and is a strength of the proposal. Reviewers felt that the Planning Approach lacked cohesion and essential detail. Although project collaborations were outlined clearly, there is little information about ongoing planning or about processes to address scientific, clinical, or regulatory issues. It is unclear how the disease team proposal will be developed or the project implemented. Reviewer Synopsis Cellular transplantation studies for congestive heart failure (CHF) have produced modest results: survival and engraftment of implanted cells is poor, and conclusive myocyte regeneration remains undemonstrated. Yet cellular and/or matrix injection approaches still reduce the loss of cardiac function after an induced infarct. Despite the mixed results, the safety and efficacy of autologous BMSC transplantation has been demonstrated; however, the process has not been optimized for promoting cell survival and preserving cardiac function. The investigators propose to address remodeling of the myocardium post AMI using a tandem stem cell and biomaterial-based approach to prevent CHF following myocardial infarction. This strategy is based upon use of stem cells within a prosurvival matrix to provide: stabilization of LV size as the artificial matrix thickens the infarct wall; reduction in border zone fiber stress associated with temporal expansion in transplant size; and, subsequent reduction in progression toward CHF. Reviewer One Comments Concept: Given the evolution of the myocardium post-infarction to a remodeled state that can provoke CHF the investigators propose to address this remodeling using a tandem stem cell and biomaterial-based approach. They will use stem cells within a prosurvival matrix to provide: 1) immediate stabilization of left ventricle (LV) size as the artificial matrix thickens the infarct wall; 2) reduction in border zone (BZ) fiber stress associated with temporal expansion in transplant size; and, 3) subsequent reduction in progression toward CHF. They refer to this as matrix-assisted myocardium stabilization (MAMS) and it aims to stabilize rather than regenerate the myocardium. The predominant early effect of MAMS arrests non-ischemic infarct extension and ventricular remodeling by thickening the infarct and thereby reducing the high systolic stress and strain in the infarct and BZ. They predict this effect will be more pronounced in the LV early after AMI rather than late after significant remodeling has already taken place. While this is an intriguing approach and it deals with an area of need in the population, there is not enough presented that indicates any readiness or near-readiness for clinical application. While bone marrow stem cells are identified as the cell source, there still appears to be the need for a great deal of interesting basic and translational large animal science before thoughts of clinical applicability can be seriously entertained. Principal Investigator: The PI has a record of excellence in the biomaterials domain, in which he has been a leader. He has experience in trans-institutional research, in working with industry and in dealing with regulatory affairs. He has presented plans for a team of investigators, has identified members of that team as well as of a steering committee. Planning Approach: There are issues here. The planning process centers around an organizational chart and a group of individuals named to head various operations. There will be biweekly meetings where team members report on findings, etc via conference calls. While mention is made of how the steering committee will provide guidance there is no cohesion regarding how the planning process will evolve, how the right type of cells/matrix will ultimately be determined, and how the interactions with FDA or industry will proceed. We are given a record of past successes, but not a roadmap for success here. And given the level of advancement of this particular field there is concern regarding readiness to compete effectively for the Disease Team Research Awards. Reviewer Two Comments Concept: • Concept / significance: A matrix-assisted myocardium stabilization approach based on the use of MSC transplantation facilitated by a pro-survival biomaterials matrix. This study is directed towards developing an effective method for preventing congestive heart failure following myocardium infarction. • Evidence and maturity: The success of this concept depends upon two elements: the development of (1) biomaterials matrix that is capable of immediate stabilization of left ventricle size, reduction in border zone fiber stress associated with temporal expansion, and subsequent reduction in progression toward congestive heart failure; and (2) stem cell populations that will facilitate the subsequent regeneration. The knowledge gap lies with the design and development of the pro-survival biomaterials component and whether the encapsulation of MSCs will improve the therapeutic outcomes. The PI expects that the planning award will help to identify MSC subpopulation, cell delivery route, large animal model, and pro-survival biomaterials. It is unclear how these will be achieved (other resources?). Principal Investigator: The PI is an established expert on biomimetic materials and surface engineering; has extensive experience in translational research and directing commercialization of his own technologies. He has experience in study stem cell-biomaterials interaction and developing biomaterials interfaces for promoting stem cell survival and expansion. The PI is well poised to direct such a multi-investigator program. Planning Approach: • The PI has laid out and identified an organized team of key players, including personnel with necessary expertise for the proposed research activities. • The coordination and collaboration activities are well thought out. • The details on developing “Disease Team Award” proposal are not discussed sufficiently to facilitate the implementation and collaboration of different expertise. • Preparation for future clinical study should be considered, e.g. GMP production and design of biomaterials components. Reviewer Three Comments Concept: Concept/ Rationale. This application proposes to investigate the possibility that stem cell transplantation coupled with biomaterials which would provide a prosurvival matrix which would provide immediate stabilization of the infarct area which would reduce the progression to congestive heart failure (CHF). The team proposes to use MSC to avoid some of the problems with immunogenicity and expansion problems associated with cardiomyocytes or hES cells. They suggest that the technology they develop would be applicable to any cell type in future studies. Maturity: The project seems to be in a preliminary state. The PI has recent publications with ES MSC and scaffold mediated renewal or directed differentiation. Nothing closely related to the present cardiac-centered application was presented. Significance. High. Cardiac therapies could create substantial financial and quality of life benefits. Principal Investigator: Kevin Healy is professor of materials science and engineering, UC Berkeley. He has received significant grant awards from NIH and other agencies and has 80 publications. He has used material design to direct bone and wound healing with success. Specific cardiac related research does not seem to have been completed. His resume reports experience with a clinical trial of an intravascular stent, a project which required the direction of 2 different companies and 3 academic institutions which is relevant to this application. Planning Approach: The approach suggests that biomaterials can assist cellular therapy by initial stabilization of the wound area followed by matrix mediated differentiation of the stem cells. A nice chart was presented to show the project collaborations. The collaborators include personnel from UC Berkeley and UCSF-VAMC. Expertise in addition to the materials lab at Berkeley includes stem cell and electrophysiology and small animal experimentation support from UCSF and pathology histology services. Details are sketchy. Scientific steering group (not advisory) include Tony Atala, a well known stem cell and regenerative medicine scientist, and individuals involved in the research including Dr. Ratcliff, Healy, Mann and Murry. External advisors like Dr. Atala might be more useful than the internal members. The PI does not seem to have planned for future clinical application. There are no clinicians identified on the application who might facilitate implementation of any developments made by the group and no discussion of how a clinical application might proceed.