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Published on: December 22, 2023
An RYR2-interacting fragment of MYBPC3 mitigates arrhythmia in human iPSC-CM and mouse models of CPVT
Fujian Lu1, Zexuan Wu1, Shaopeng Chi1
1Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA.
Abstract:
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia caused by pathogenic variants in RYR2 that increase its diastolic Ca2+ release. Current standard of care is insufficient to protect patients from ventricular tachycardia (VT) and sudden death. We identified RYR2 interaction with a subset of MYBPC3 in cardiomyocytes and validated this interaction by immunostaining, proximity ligation assay, and co-immunoprecipitation. Adeno-associated virus serotype 9 (AAV9)-mediated MYBPC3 overexpression reduced VT in Ryr2R176Q/+ mice, a model of CPVT. We identified a C-terminal fragment of MYBPC3, C6C10Δ, that is sufficient for RYR2 interaction and anti-arrhythmic activity. Recombinant C6C10Δ reduced the probability of open RYR2-R176Q channels in lipid bilayer single-channel recordings, and virally delivered C6C10Δ reduced VT inducibility and duration in the CPVT mouse model and in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) harboring several different CPVT-causing RYR2 variants. In wild-type mice, MyoAAV4E-C6C10Δ did not detectably affect cardiac morphology or systolic function. However, a proportion of MyoAAV4E-C6C10Δ-treated wild-type mice exhibited inducible VT, suggesting pro-arrhythmic potential that warrants further study. Together, these findings demonstrate that a subset of MYBPC3 interacts with RYR2 and that this interaction may be therapeutically exploited to develop CPVT gene therapy.
Insights
A novel gene therapy approach using a MYBPC3 fragment shows promise for treating catecholaminergic polymorphic ventricular tachycardia (CPVT). This therapy targets RYR2 interactions to reduce dangerous heart arrhythmias and sudden death in CPVT patients.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Genetic Medicine
Background:
- Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited arrhythmia.
- Pathogenic RYR2 variants cause CPVT by increasing diastolic calcium release.
- Current treatments for CPVT are inadequate, leading to significant mortality.
Purpose of the Study:
- To investigate the interaction between RYR2 and MYBPC3 in cardiomyocytes.
- To explore the therapeutic potential of targeting this interaction for CPVT treatment.
- To develop a gene therapy strategy for CPVT using MYBPC3.
Main Methods:
- Identified and validated RYR2-MYBPC3 interaction using molecular biology techniques.
- Utilized adeno-associated virus serotype 9 (AAV9) for gene delivery in CPVT mouse models.
- Performed single channel recordings and assessed cardiac function in treated animals and human cells.
Main Results:
- Overexpression of MYBPC3 reduced ventricular tachycardia (VT) in a CPVT mouse model.
- A specific MYBPC3 fragment (C6C10Δ) demonstrated anti-arrhythmic activity by reducing RYR2 channel open probability.
- Virally delivered C6C10Δ reduced VT inducibility and duration in CPVT models, including human iPSC-CMs.
- No significant adverse effects on cardiac function were observed in wild-type mice, though proarrhythmic potential requires further investigation.
Conclusions:
- A subset of MYBPC3 interacts with RYR2, offering a new therapeutic target for CPVT.
- MYBPC3-based gene therapy, particularly using the C6C10Δ fragment, shows significant potential for treating CPVT.
- This interaction provides a foundation for developing novel gene therapies to prevent sudden death in CPVT patients.
