Advantages
- The introduction of PKP2 genes into iPS cell-derived PKP2 mutant cardiomyocytes in patients with ARVC disease improved the disease condition, demonstrating the potential of gene and mRNA therapy
- An in vitro assay that reproduces the patient’s pathophysiology is feasible using patient-derived PKP2 mutant cardiomyocytes, isogenic cardiomyocytes that have recovered PKP2 mutations, and beating cardiomyocytes
- Similar cell models and data are available for other genes involved in ARVC
Background and Technology
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare intractable disease that presents with thinning and enlargement of the right ventricular myocardium, leading to fatal arrhythmias such as ventricular tachycardia and ventricular fibrillation. Intercalated disc gene abnormalities are the major known causes of ARVC and, among them, plakophilin2 (PKP2) is the most frequently identified mutant gene that causes ARVC. PKP2 knockout mice develop myocardial structural abnormalities and ventricular wall rupture during embryonic development, indicating that PKP2 is an important factor in cardiac development.
Cardiomyocytes that differentiate from ARVC patient-derived diseased iPS cells (iPSC) with PKP2 mutations (iPSC-CMs) reportedly have decreased intercalated disc-related proteins, abnormal lipid droplet deposition, prolonged time to increase in action potential, and increased expression of PPARγ compared to iPSC-CMs derived from healthy individuals. However, all previous reports have been comparisons to iPSC-CMs derived from healthy individuals with different genetic backgrounds, and there is no human disease model cell set that can be used to accurately evaluate the pathophysiology caused by PKP2 gene abnormalities by modifying only PKP2 gene mutations in the same genetic background. In addition, there have been no pathological models mimicking beating cardiomyocytes, instead of single myocardium, reported to date.
In this study, isogenic iPS cells with mutations and modifications in only the PKP2 gene and cardiomyocytes differentiated from these cells have been established in the same genetic background, and these cells reproduced the pathophysiology of ARVC in humans. These model cells demonstrate the therapeutic concept of gene replacement and mRNA therapy since the disease condition improved with restoration of the PKP2 gene. Moreover, these isogenic cells are useful models for gene and mRNA therapy development for ARVC.
Data
Experimental data showing that the introduction of PKP2 genes into NHEJ iPS-differentiated myocardium using adeno-associated viruses suppresses progression to reticulated myocardial structures and decreased contractility
Modeling reduced contractility and impaired desmosome assembly due to plakophilin-2 deficiency using isogenic iPS cell-derived cardiomyocytes
https://doi.org/10.1016/j.stemcr.2021.12.016
Related information of the researcher’s study
Phenotypic recapitulation and correction of desmoglein-2-deficient cardiomyopathy using human-induced pluripotent stem cell-derived cardiomyocytes
https://doi.org/10.1093/hmg/ddab127
Expectations
The proposal is regarding a partnership on gene therapy and/or mRNA therapy development for ARVC using ARVC patient-derived iPS cells and isogenic cells owned by Osaka University. The university provides the cells and know-how under an agreement with a company.
Product No. DA-03254