Most heart conditions leading to sudden death or impaired cardiac pumping 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. One of these inherited heart diseases is named arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The signature features of sick ARVD/C hearts are progressive heart muscle loss and their replacement by fat and scare tissues, which can lead to lethal irregular heart rhythms and/or heart failure. We have made a significant breakthrough and successfully modeled the sick ARVD/C heart muscles within two months in cell cultures using versatile stem cells derived from ARVD/C patients’ skin cells with genetic mutations in one of the desmosomal (a specific type of cell-cell junctions in hearts) proteins, named plakophilin-2. These disease-specific stem cells can give rise to heart cells, which allow us to discover specific abnormalities in heart energy consumption of ARVD/C heart muscles that causes dysfunction and death of these diseased heart cells. In the Year 1 of this grant support, we have made and characterized additional stem cells lines from ARVD/C patients with different desmosomal mutations. We are in the process to determine if heart muscles derived from these new ARVD/C patient-specific stem cells have common disease-causing mechanisms as we had published. We found two proposed therapeutic agents are ineffective in suppressing ARVD/C disease in culture but we have identified one potential drug that suppressed the loss of ARVD/C heart cells in culture. We also started to establish a known ARVD/C mouse model for future preclinical drug testing.
Reporting Period:
Year 2
Most heart conditions leading to sudden death or impaired cardiac pumping 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. One of these inherited heart diseases is named arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The signature features of sick ARVD/C hearts are progressive heart muscle loss and their replacement by fat and scare tissues, which can lead to lethal heart rhythms or heart failure. We made significant breakthrough and successfully modeled sick ARVD/C heart muscles in cell cultures using versatile stem cells derived from ARVD/C patients’ skin cells with genetic mutations in desmosomal (a specific type of cell-cell junctions in hearts) proteins, e.g. plakophilin-2 (Pkp2). These disease-specific stem cells can give rise to heart cells, which allow us to discover specific abnormalities in energy consumption of ARVD/C heart muscles that lead to their dysfunction and death. In Year 2, we continued to create and characterize additional stem cells lines from ARVD/C patients with different desmosomal mutations. As we had published previously, we have confirmed that the same metabolic deregulation occurs in heart muscles derived from new ARVD/C patient-specific stem cells with different mutations from Pkp2. We further explored new microRNA-based pathogenic mechanisms and identified new classes of therapeutic agents to suppress ARVD/C pathologies in culture. We also started to establish a known ARVD/C mouse model for future preclinical drug testing.
Reporting Period:
Year 3
Most heart conditions leading to sudden death or impaired heart pumping 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 heart dysfunction. One of these inherited heart diseases is named arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/C). The signature features of sick ARVD/C hearts are progressive heart muscle loss and their replacement by fat and scar tissues, which can lead to lethal irregular heart rhythms or heart failure. We made significant breakthrough and successfully modeled sick ARVD/C heart muscles in cell cultures using versatile stem cells derived from ARVD/C patients’ skin cells with genetic mutations in desmosomal proteins (a specific type of cell-cell junctions in hearts), e.g. plakophilin-2 (Pkp2). These disease-specific stem cells can give rise to heart cells, which allow us to discover specific abnormalities in energy consumption of ARVD/C heart muscles that lead to their dysfunction and death. In Year 3, we have created and characterized additional stem cells lines from ARVD/C patients with different desmosomal mutations from Pkp2 mutations. We confirmed that the same metabolic deregulation occurred in heart muscles derived from new ARVD/C patient-specific stem cells with different mutations from Pkp2. Most importantly and in the Year 3, we cracked the disease codes and elucidated the entire key pathogenic networks underlying how mutations in Pkp2 lead to metabolic derangement in ARVD/C heart cells. Based on these novel findings, we have identified two potential and clinically safe prototype drugs that may slow down ARVD/C disease progression. We have requested a 7-month extension so that we could test these two new prototype drugs in their efficacy of treating an established ARVD/C mouse model so that we could obtain animal therapeutic and toxicity data in preparation for future clinical therapeutic testing in human patients with ARVD/C.
Reporting Period:
Year 4/NCE
Most heart conditions leading to sudden death or impaired heart pumping 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 heart dysfunction. One of these inherited heart diseases is named arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). The signature features of sick ARVD/C hearts are progressive heart muscle loss and their replacement by fat and scar tissues, which can lead to lethal irregular heart rhythms or heart failure. We made significant breakthrough and successfully modeled sick ARVD/C heart muscles in cell cultures using versatile stem cells derived from ARVD/C patients’ skin cells with genetic mutations in desmosomal proteins (a specific type of cell-cell junctions in hearts), e.g. plakophilin-2 (Pkp2), desmoplakin (Dsp), etc. Using heart cells derived from ARVD/C-specific stem cells, we discover specific abnormalities in energy consumption of ARVD/C heart muscles that lead to their dysfunction and death. We have generated and characterized additional stem cells lines from ARVD/C patients with different desmosomal mutations from Pkp2 mutations. We confirmed that the same metabolic deregulation occurred in heart muscles derived from new ARVD/C patient-specific stem cells with different mutations from Pkp2. Most importantly, we have cracked the disease codes and elucidated the entire key pathogenic networks underlying how mutations in Pkp2 lead to metabolic derangement in ARVD/C heart cells. Based on these novel findings, we identified and tested two potential clinically safe drugs in their efficacy of treating an established ARVD/C mouse model. We found that these two drugs are effective in reducing deterioration of cardiac function in ARVD/C mice, which will be the foundation for future clinical therapeutic testing in human patients with ARVD/C. This is the first time that a patient-specific stem cell based in-vitro model leads to novel pathogenic insights and to permit the development of novel ARVD/C-specific therapies in vivo.
Grant Application Details
Application Title:
Studying Arrhythmogenic Right Ventricular Dysplasia with patient-specific iPS cells
Public Abstract:
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.
Statement of Benefit to California:
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.
