Tools and Technologies I
Cardiovascular disease is the leading cause of mortality and morbidity in the United States and is predicted to be a leading cause of death worldwide. Each year, over 19 million incidents of sudden cardiac events occur worldwide, with approximately 1 million of those in the United States. Despite the advances in medical treatment and interventional procedures to reduce mortality in patients with acute coronary syndrome, the number of patients with refractory myocardial ischemia and congestive heart failure is rapidly increasing. Currently, heart transplantation is the only successful treatment for end-stage heart failure; however, the ability to provide this treatment is limited by the availability of donor hearts. There is an urgent need to develop alternative therapies for both acute myocardial infarction and chronic cardiomyopathies. Recent work indicates that stem cells delivered via direct intramyocardial injection or intracoronary injection following acute MI have produced mixed results showing improvement of LV function of injured myocardium in humans with one study demonstrating sustained benefit; but other studies producing negative trials or transient benefit. The reasons for failure to translate preclinical results into benefits in humans are not known, but a good candidate is the vast difference in cell number required for human therapy compared to rodents. Additionally, advocates recognize major limitations due to lack of specific means to deliver the cells efficiently and effectively. Human antibodies for identification, selection and specific delivery of therapeutic stem cells will be developed. The identification and isolation of a specific human embryonic stem cell derived heart muscle antibodies would be a significant milestone since there presently are no human specific antibodies for human embryonic stem cell derived heart muscle. The isolation of antibodies will be a technical advancement to allow for the identification and potentially lead to selection techniques which will overcome one of the major hurdles of human embryonic stem cell derived heart muscle which is obtaining adequate numbers to be transplanted. The development of an antibody technology that will deliver the stem cells specifically to the area of a heart attach and/or beneficially influence the local tissue environment will enhance the field of myocardial regeneration. The developed technology can be potentially adapted to other organs as a tool for tissue regeneration.
Statement of Benefit to California:
The funding from the CIRM grant will lead to critical proof of concept studies regarding the utility of our “targeting” technology for stem cells in myocardial repair. Cardiovascular disease is the leading cause of mortality and morbidity in California and the United States. Myocardial infarctions are also a leading cause of premature, permanent disability in the labor force, accounting for 19 percent of disability allowances by the Social Security Administration. Therapies directed at preventing and treating congestive heart failure resulting from myocardial infarctions would help reduce the social and economic impact from lost wages as well as reducing costs to the healthcare system. The benefit to the California economy will arise from the ongoing product development. The technology being developed creates a new line of tools for regenerative medicine. The technology builds and expands on the biotechnology sector and will lead to products used clinically to initially treat cardiovascular patients. Additionally, the technology being developed can be used for stem cell isolation and separation kits. The optimization of the antibodies would lead to the creation of new jobs within California. The commercialization of the antibody targeted stem cell therapy could potentially lead to a new industry within California. As part of the process of developing a therapeutic product, jobs will be created at academic centers and the private sector to demonstrate proof of concept studies as well as regulatory, preclinical testing, manufacturing, sales and clinical trials.
This proposal focuses on the development of a novel tool for identifying therapeutic stem cells, targeting them to a specific site, and then retaining them at that location while they provide regenerative functions. In the first aim, the applicants will identify and isolate high affinity antibodies that bind to human embryonic stem cell (hESC)-derived mature adult cardiomyocytes. In the second aim, multifunctional antibodies will be generated that are capable of binding simultaneously to hESC-derived cardiomyocytes and antigens that are specific to the targeted microenvironment. The applicant further proposes a new technologic approach to influence the local tissue environment. In the third aim, the applicants will evaluate the performance of these new tools both for targeting and for therapy using an ischemia-perfusion clinical model of myocardial infarction. The reviewers were enthusiastic about the technology in this proposal, a portion of which appears feasible based on preliminary data and the proven capabilities of the research team. However, the ambitious scope and complexity of the project were of concern to the reviewers, who worried that the defined milestones could not be achieved in the designated time frame. In addition, reviewers noted a few significant oversights in the research plan that could diminish the chance for success. Finally, the stated budget was inaccurate due to conflicting figures presented for supplies. Most reviewers felt that the impact of this proposal would be high, as successful targeting and retention of therapeutic stem cells at designated sites has been a major hurdle in this field. One reviewer felt that the antibody approach is based on prior proof of concept studies and thus does not make a new contribution to basic stem cell biology, although a successful outcome would represent a moderate medical advance and contribute to translational research. The major impact of this effort would derive from the technology as a platform rather than the potential for new cardiotherapy. The reviewers had mixed feelings about the feasibility of this proposal. The strongest points were the capabilities and expertise of the research team, who have already established proof of principle for a similar, but less complex approach, and offered compelling preliminary data. Several concerns were raised about Aim 1, the success of which depends on the identification of antibodies that bind to mature, but not to immature cardiomyocytes. One reviewer noted that the concept depends upon targeting mature hESC-derived cardiomyocytes as the therapeutic cell product. However, the proposal did not detail what constituted a “mature” cardiomyocyte, and success of the strategy depends on the investigators’ ability to define surface antigens specific to maturation states. Of further concern, the applicants did not take into consideration the gender of the stem cell population or that of the recipient. Recent studies have shown that engraftment of stem cells is dependent on the gender of the donor cell. While most reviewers felt that Aim 2 was within the expertise of the research team, the scope seemed ambitious given the limited time for completion. Reviewers expressed concern that a customary battery of in vitro assays was not proposed for the reagents generated in aim 2 before moving into expensive in vivo studies. Finally, one reviewer commented that the premise that microenvironmental cues can be regulated by the proposed new approach requires more study. Aim 3 was the most problematic and was described as poorly designed and inadequate. The in vivo experiments were judged to be poorly designed, with no iterative analysis. The applicant did not include vehicle or sham controls, which are essential to accurately interpret the validity of their experiments. The research team comprises a public/private partnership that seems well poised to conduct this research. The principal investigator is a renowned cardiologist with extensive experience in cardiovascular tissue engineering. The reviewers felt that the additional investigators were qualified and capable of performing this research. Reviewers could not determine the appropriateness of the budget because of a discrepancy in the text of the proposal. Overall, the proposed technology is promising but of questionable feasibility, largely due to the technically complex aims, overly ambitious scope, and poorly designed validation strategy.