Grant Award Details
- Development of a large animal (macaca mulatta) model for predictive preclinical testing of engineered cardiac autografts and allografts.
Grant Application Details
- Advanced animal model for predictive preclinical testing of engineered cardiac autografts and allografts
Heart disease is the number one cause of death in the US. Heart muscle injured during a heart attack does not regenerate, and the resulting damage leads to heart failure, which inflicts almost 6 million people in the US alone. Recently, several studies have shown that direct injection of stem cell-derived heart cells may offer regenerative potential in the damaged heart. However, injected heart cells often lack the spatial and temporal organization required to create uniform tissue with synchronized beating, while rapid donor cell death poses another key limitation. For these reasons, we propose to transplant engineered heart muscle (EHM) that is spatially and temporally organized into a relevant large animal model. Our proposal addresses unique translational challenges pertaining to tissue engineered heart repair by scaling our established human induced pluripotent stem cell (iPSC) differentiation protocol to create one billion human and large animal model cardiomyocytes for each EHM, in order to meet clinical demands by: (1) adopting our established human EHM tissue engineering process to the large animal model; (2) defining conditions for EHM implantation; and (3) performing a pivotal feasibility, safety, and efficacy study in the large animal model with chronic heart failure. Our studies will establish long-term safety and efficacy of iPSC-EHM therapies in a clinically relevant large animal model, which will overcome a major unresolved bottleneck to the translation of stem cell therapies to humans.
Cardiovascular disease (CVD) affects more than 1.7 million Californians. The societal and financial costs are tremendous, with CVD accounting annually for an estimated $8 billion in California health care costs alone. Following a heart attack, the endogenous regenerative process is not sufficient to compensate for heart tissue death. Thus, using regenerative therapies with human stem cells to form engineered heart tissue is emerging as a promising therapeutic avenue. Engineered tissues are already being used in patients needing artificial blood vessels, bladders, and tracheas. Our multidisciplinary team proposes to create human engineered heart tissue (EHT) for treatment of post-attack heart failure in a clinically-enabling large animal model, and we are confident we will be able to move our potential therapy into preclinical human trials. Development of therapies for diseases such as CVD could potentially improve the California health care system by reducing the long-term health care cost burden on California. In addition, our research may provide an opportunity for California to benefit from royalties, patents, and licensing fees, which will create cutting-edge projects, attractive jobs, and innovative therapies that will generate millions of dollars in new tax revenues and opportunities in our state. Finally, our research could further advance the flourishing biotech industry in California, serving as a crucial engine to power California’s economic future.
- Stem Cell Reports (2018) Comparison of Non-human Primate versus Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Treatment of Myocardial Infarction. (PubMed: 29398480)
- Biomaterials (2017) Contractile force generation by 3D hiPSC-derived cardiac tissues is enhanced by rapid establishment of cellular interconnection in matrix with muscle-mimicking stiffness. (PubMed: 28384492)
- Stem Cells (2017) Comparison of Non-Coding RNAs in Exosomes and Functional Efficacy of Human Embryonic Stem Cell- versus Induced Pluripotent Stem Cell-Derived Cardiomyocytes. (PubMed: 28710827)
- Stem Cells (2017) Brief Report: External Beam Radiation Therapy for the Treatment of Human Pluripotent Stem Cell-Derived Teratomas. (PubMed: 28600830)
- Biomaterials (2017) Bioacoustic-enabled patterning of human iPSC-derived cardiomyocytes into 3D cardiac tissue. (PubMed: 28376365)
- Nat Rev Drug Discov (2017) Induced pluripotent stem cell technology: a decade of progress. (PubMed: 27980341)
- Circulation (2017) Defined Engineered Human Myocardium With Advanced Maturation for Applications in Heart Failure Modeling and Repair. (PubMed: 28167635)
- Circ Res (2017) 3-Dimensionally Printed, Native-Like Scaffolds for Myocardial Tissue Engineering. (PubMed: 28408446)
- Adv Drug Deliv Rev (2016) Engineered heart tissues and induced pluripotent stem cells: Macro- and microstructures for disease modeling, drug screening, and translational studies. (PubMed: 26428619)
- JAMA Cardiol (2016) Adult Stem Cell Therapy and Heart Failure, 2000 to 2016: A Systematic Review. (PubMed: 27557438)
- JAMA Cardiol (2016) Potential Strategies to Address the Major Clinical Barriers Facing Stem Cell Regenerative Therapy for Cardiovascular Disease: A Review. (PubMed: 27579998)
- Stem Cell Reports (2016) Comparison of Magnetic Resonance Imaging and Serum Biomarkers for Detection of Human Pluripotent Stem Cell-Derived Teratomas. (PubMed: 26777057)
- Circ Res (2015) Human Engineered Heart Muscles Engraft and Survive Long-Term in a Rodent Myocardial Infarction Model. (PubMed: 26291556)