Most heart conditions leading to sudden death or impaired pumping heart functions in the young people (<35 years old) are the results of genetic mutations inherited from parents. It is very difficult to find curative therapy for these inherited heart diseases due to late diagnosis and lack of understanding in how genetic mutations cause these diseases. Using versatile stem cells derived from patients’ skin cells with genetic mutations in cell-cell junctional proteins, we have made a significant breakthrough and successfully modeled one of these inherited heart diseases within a few months in cell cultures. These disease-specific stem cells can give rise to heart cells, which allow us to discover novel abnormalities in heart energy consumption that causes dysfunction and death of these diseased heart cells. Currently, there is no disease-slowing therapy to these inherited heart diseases except implanting a shocking device to prevent sudden death. We propose here to generate more patient-specific stem cell lines in a dish from skin cells of patients with similar clinical presentations but with different mutations. With these new patient-specific stem cell lines, we will be able to understand more about the malfunctioned networks and elucidate common disease-causing mechanisms as well as to develop better and safer therapies for treating these diseases. We will also test our new therapeutic agents in a mouse model for their efficacy and safety before applying to human patients.
Heart conditions leading to sudden death or impaired pumping functions in the young people (<35 years old) frequently are the results of genetic mutations inherited from parents. Currently, there is no disease-slowing therapy to these diseases. It is difficult to find curative therapy for these diseases due to late diagnosis. Many cell culture and animal models of human inherited heart diseases have been established but with significant limitation in their application to invent novel therapy for human patients. Recent progress in cellular reprogramming of skin cells to patient-specific induced pluripotent stem cells (iPSCs) enables modeling human genetic disorders in cell cultures. We have successfully modeled one of the inherited heart diseases within a few months in cell cultures using iPSCs derived from patients’ skin cells with genetic mutations in cell-cell junctional proteins. Heart cells derived from these disease-specific iPSCs enable us to discover novel disease-causing abnormalities and develop new therapeutic strategies. We plan to generate more iPSCs with the same disease to find common pathogenic pathways, identify new therapeutic strategies and conduct preclinical testing in a mouse model of this disease. Successful accomplishment of proposed research will make California the epicenter of heart disease modeling in vitro, which very likely will lead to human clinical trials and benefit its young citizens who have inherited heart diseases.
This proposal aims to take advantage of iPSC technology to both explore the mechanism of and identify potential treatments for the genetic heart disease arrythmogenic right ventricular dysplasia (ARVD). In ARVD, heart muscle is lost and replaced by fatty tissue, which can result in sudden death from arrhythmia. The applicants have generated and identified an in vitro phenotype in patient iPSC-CM and plan to generate additional patient lines and test their phenotypes in vitro. Next, the group plans to test modulators of key signaling pathways in order to prevent development of the ARVD in vitro phenotype. Finally, the team plans to test these potential therapeutics in an in vivo disease model for both efficacy in preventing development of the disease phenotype and for overt systemic toxicity.
Significance and Innovation
- There are no treatments to modify the course of ARVD. This work could result in directly translatable findings and ultimately have a high impact.
- Reviewers highlighted the need for better models of ARVD and were encouraged that the PI’s patient based iPSC models generated under this award could fill this gap.
- The panel appreciated the applicant’s use of innovative techniques to model ARVD.
- The clinical impact of the therapeutic work described in the application will be upon those patients with early stage disease.
Feasibility and Experimental Design
- Reviewers were especially impressed by the compelling preliminary data supporting the team’s ability to perform the proposed experiments and the program’s likelihood for success.
- The panel noted that new patient iPSC lines might not replicate the observations of the original line.
- The proposal acknowledged potential problems and proposed alternative approaches and solutions.
Principal Investigator (PI) and Research Team
- The PI is a productive, established and respected investigator with direct expertise in the area of the proposed studies.
- The strong collaborative assembled team has the appropriate expertise to successfully execute the plan.
Responsiveness to the RFA
- Reviewers found the proposal to be highly responsive to the RFA.