Early Translational IV
$2 239 785
Our long-term goal is to use stem cells derived from skin cells (iPS cells) to repair damaged heart tissue and ultimately to cure heart failure. In order to make this process safer, we propose to make a series of heart tissue diagnostic assays (HT-Dx) to help identify the cells that will have unwanted effects, before they are ever used on people. There is a great need for heart cell treatments, since many people are dying of heart failure. However, this process is also complicated since the heart is complex and many things could cause unwanted side effects. One problem is the cells might not survive after transplantation and cause scars. Another problem is that the cells could beat in the wrong way, causing the heart to beat abnormally (known as arrhythmia). The HT-Dx assays will allow us to grow heart tissue “on a chip” so that we can simulate heart cell transplants and determine how different cell types will behave in a transplant setting. By carefully measuring how the transplanted cells work in the HT-Dx, we hope to tell which cell lines would be most successful, even before being transplanted in a person. For instance, a person with heart failure might be able to choose between twenty different stem cell lines, and the HT-Dx could help the doctors choose the stem cell line that would do the best job. If the HT-Dx is successful, we will have safer, more effective cardiac cell transplants in the future. We hope that his will be an important step in curing heart failure.
Statement of Benefit to California:
We aim to make the process of repairing damaged heart tissue safer by developing a series of heart tissue diagnostic assays, to identify the stem cell populations most likely to have adverse effects following transplantation before they are ever used in people. This research can benefit California in several ways. The results from our studies could facilitate new technology development within the California biotechnology industry. Our assays could provide valuable diagnostic tools to be used by biotechnology companies and hospitals in California. Furthermore, our Cardiac Reference Panel of iPS cell lines could be used for comparing and optimizing assays, which could be invaluable for biotechnology companies and researchers screening cell lines and drug compounds. We are working closely with California companies to develop new materials, microscopes, assay devices, and analytical software that could be the basis for new product lines or new businesses. If therapies do come to fruition, we anticipate that California medical centers will lead the way. Finally, the most important contribution of this study would be to improve the health of Californians by improving the predictability of success of cell transplantation. Heart disease is a major cause of mortality and morbidity in California, resulting in billions of dollars in health care costs. Our goal is to improve quality of life and increase productivity for the millions who suffer from heart disease.
This Development Candidate Feasibility (DCF) proposal aims to develop a set of in vitro cardiac microtissue-based assays. This technology is intended to mimic transplantation of donor cardiomyocytes in the context of recipient cells and thereby supplement preclinical in vivo studies. As an essential component of this assay set, the applicant plans to develop a reference panel of various human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) samples, including cells bearing known mutations that are prone to arrhythmias. They will then use this cell panel and the assays to test the in vitro behavior of the various hiPSC-CM preparations, such as extent of cell:cell coupling and normal or abnormal beating. The applicant envisions that this set of assays and reference standards could ultimately identify potentially unsafe iPSC-CM preparations and enable the selection of safe cell populations for therapeutic use. Objective and Milestones - Rather than a TPP for a clinically applicable development candidate, the application presents an abstract of a program to develop an in vitro cell screening technology. - This tool could provide interesting information about electrical coupling of cells, but may not inform clinical benefits of cell populations chosen for transplantation. Rationale and Significance - The intended indication is not clinical. The applicant’s stated use for the proposed technology is to streamline preclinical testing, rather than to provide a diagnostic or cell-based therapy for clinical use. - - It is unclear whether the tool will be an improvement to existing in vitro methods (such as patch clamp). - The proposed assays do not address the effects that fibrosis present in failing hearts would have upon transplanted cell populations. The suggestion was made that the applicant address the milieu following ischemic injury to improve the utility of this technology for the selection of optimized cells for transplantation. Feasibility and Design - Proof of concept for a development candidate will not be achieved, as neither a diagnostic nor a potential therapeutic DC is proposed. - The plan lacks discussion of the candidate assays’ sensitivity and specificity. - Plans to establish that the proposed in vitro tests predict in vivo results are lacking. Reviewers felt this limited the ability of the technology to generate interpretable data. - Reviewers described the application as poorly worded and difficult to follow. - Preliminary data largely supports the applicant’s ability to perform the proposed studies. However, it was unclear that the applicant would be able to achieve the milestones during the award period. Qualifications of the PI and Team - The PI is clearly an expert in cardiomyocyte biology, but the construction of the proposal suggests that the team lacks expertise in development of a diagnostic test as the proposal is for a research tool. Collaborations, Assets, Resource and Environment - The proposed bioengineering collaboration is critical to the success of the proposed program. Responsiveness to the RFA - The panel unanimously agreed the application was not responsive to the RFA. It describes development of a tool to assess hiPSC-CM rather than a clinical or diagnostic development candidate. This was a critical factor in the scoring of the application.