Familial hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death in young people, including trained athletes, and is the most common inherited heart defect. Until now, studies in humans with HCM have been limited by a variety of factors, including variable environmental stimuli which may differ between individuals (e.g., diet, exercise, and lifestyle), the relative difficulty in obtaining human cardiac samples, and inadequate methods of maintaining human heart tissue in cell culture systems. Cellular reprogramming methods that enable derivation of human induced pluripotent stem cells (hiPSCs) from adult cells, which can then be differentiated into cardiomyocytes (hiPSC-CMs), are a revolutionary tool for creating disease-specific cell lines that may lead to effective targeted therapies.
In this proposal, we will derive hiPSC-CMs from patients with HCM and healthy controls, then perform a battery of functional and molecular tests to determine the presence of cardiomyopathic disease and associated abnormal molecular programs. With these preliminary studies, we believe hiPSC-CMs with HCM phenotype will dramatically enhance the ability to perform future high-throughput drug screens, evaluate gene and cell therapies, and assess novel electrophysiologic interventions for potential new therapies of HCM. Because HCM is not a rare disease but rather the leading cause of inherited heart defects, we believe the findings here should have broad clinical and scientific impact toward understanding the molecular and cellular basis of HCM.
Familial hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death in young people and is the most common inherited heart defect. In this study, we will generate hiPSC-derived cardiomyocytes from patients with HCM, then perform a number of functional, molecular, bioinformatic, and imaging analyses to determine the extent and nature of cardiomyopathic disease. We believe hiPSC-CMs with HCM phenotype will dramatically enhance the ability to perform future high-throughput drug screens, evaluate gene and cell therapies, and assess electrophysiologic interventions for potential novel therapies of HCM. The experiments outlined are pertinent and central to the overall mission of CIRM, which seeks to explore the use of stem cell platforms to yield novel mechanistic insights into the molecular and cellular basis of disease. Because HCM is not an orphan disease, but rather the leading cause of sudden cardiac death in young people, we believe the research findings will benefit the state of California and its citizens.
The applicant proposes to develop an in vitro model of inherited hypertrophic cardiomyopathy (HCM) using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) from patients with known mutations and from healthy family members as controls. The applicant plans to use a range of electrophysiological and molecular pharmacology techniques to determine if patient hiPSC-CM recapitulate the disease phenotype in vitro. Clinical antiarrhythmic drugs will also be tested for the ability to modulate in vitro arrhythmias observed in this disease model. Finally, to prove that the observed phenotypes are caused by the known mutations, rather than by secondary or unrelated defects, the applicant will perform rescue experiments correcting the defective locus through gene targeting.
Significance and Innovation:
- HCM is a leading cause of sudden cardiac death with few relevant human disease models available to test for better treatments. Therefore, the proposed research is highly significant.
- The potential impact of the work is high as it could ultimately lead to improved treatment of HCM by enabling the identification of more effective antiarrhythmic compounds for this disease.
Feasibility and Experimental Design:
- The extensive and compelling preliminary data demonstrate the feasibility of the proposal and its potential for impacting disease, including demonstrating the following: access consented patients, the ability to generate patient hiPSCs and differentiate them to cardiomyocytes, and the ability to detect defects in patient hiPSC-CM and modulate defects with drugs in vitro.
- The competition in cardiac disease modeling using hiPSCs is substantial. However, the applicant is well positioned to impact the field.
- The application was described as clear-cut, state of the art, and excellent.
- Impedence measurement was suggested as an alternate, more authentic force measurement technique rather than the technique proposed in the application.
- The genetic rescue experiment is commendable.
Principal Investigator (PI) and Research Team:
- The PI was described as a well-funded rising star with extensive hiPSC and cardiac expertise and a strong, relevant publication record.
- The assembled extraordinary research team has all the techniques and expertise in place to perform the proposed studies.
Responsiveness to the RFA:
- The proposal is focused on utilizing a hiPSC-derived cell population to develop a disease-in-a-dish model and to study aspects of underlying disease mechanism. The project is highly responsive to the RFA.