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Updated: Mar 5, 2026
Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk
Published on: July 27, 2022
Viral delivered gene therapy to treat catecholaminergic polymorphic ventricular tachycardia (CPVT2) in mouse models
Efrat Kurtzwald-Josefson1, Dor Yadin1, Shiraz Harun-Khun2
1Leviev Heart Center, Sheba Medical Center, Tel Hashomer and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Cardiac Research Lab, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Background:
The recessive form of catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2) is caused by mutations in cardiac calsequestrin (CASQ2), leading to protein deficiency.
Objectives:
The aims of this study were to develop a viral-delivered gene therapy for CPVT2 and to determine the relationship between CASQ2 expression and antiarrhythmic efficacy in a murine model.
Methods:
We used a murine model of CPVT2 caused by the D307H human mutation (CASQ2D307H) or CASQ2 knockout (CASQ2Δ/Δ). Adeno-associated virus (AAV) particles containing the CASQ2 gene (AAVCASQ2) were injected into the heart or intraperitoneally to 12-week-old mice. A telemetry device was implanted, and mice underwent provocation testing 7-8 weeks after gene therapy.
Results:
CASQ2Δ/Δ mice injected intracardiacally with AAVCASQ2 expressed 40% ± 25% of the normal CASQ2 protein level, which was increased compared to untreated CASQ2Δ/Δ mice (n = 10; P < .05). Intraperitoneal therapy led to a significantly elevated expression of the CASQ2 protein, which was comparable in CASQ2D307H (n = 12) and CASQ2Δ/Δ (n = 4) mice. All control mice with CPVT2 had nonsustained ventricular tachycardia (VT) and 8 of 13 had sustained VT on provocation. Expressing ≥33% of the normal CASQ2 level was needed to protect from nonsustained VT as well as stress-induced premature ventricular contractions. Lower levels of expression prevented sustained VT in AAVCASQ2-treated mice (0 of 26; P < .001 vs controls).
Conclusion:
AAVCASQ2 displays a long-lasting capacity to attenuate and potentially cure CPVT2. Systemic delivery is feasible and convenient, reproducibly providing adequate levels of transgene expression. Antiarrhythmic efficacy depends on the CASQ2 level: ≥33% of the normal CASQ2 level is needed to prevent arrhythmia. However, even lower levels of protein protect from sustained VT, thereby potentially reducing the risk of sudden death.
Insights
Gene therapy using adeno-associated virus (AAV) successfully restored cardiac calsequestrin (CASQ2) levels in a mouse model of catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2). This treatment significantly reduced arrhythmias, offering a potential cure for CPVT2.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Gene Therapy
Background:
- Catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2) is a genetic heart rhythm disorder.
- It is caused by mutations in the cardiac calsequestrin (CASQ2) gene, leading to a deficiency in the CASQ2 protein.
Purpose of the Study:
- To develop a viral-delivered gene therapy for CPVT2.
- To investigate the correlation between CASQ2 protein expression and antiarrhythmic effectiveness in a mouse model.
Main Methods:
- A murine model of CPVT2 was utilized, employing either a human D307H mutation or a CASQ2 knockout.
- Adeno-associated virus (AAV) carrying the CASQ2 gene (AAVCASQ2) was administered via intracardiac or intraperitoneal injection.
- Mice were monitored using telemetry, with provocation testing conducted post-therapy.
Main Results:
- Intracardiac AAVCASQ2 therapy in CASQ2 knockout mice restored CASQ2 protein levels to approximately 40%.
- Intraperitoneal therapy also significantly increased CASQ2 expression in both CPVT2 models.
- Expression of at least 33% of normal CASQ2 levels protected against non-sustained ventricular tachycardia (VT).
- Lower CASQ2 levels prevented sustained VT in treated mice, reducing sudden death risk.
Conclusions:
- AAVCASQ2 gene therapy demonstrates long-lasting potential to treat and possibly cure CPVT2.
- Systemic delivery via AAV is a feasible and convenient method for achieving therapeutic CASQ2 expression.
- Antiarrhythmic efficacy is dose-dependent, with higher CASQ2 levels preventing all arrhythmias, while lower levels still mitigate life-threatening sustained VT.
