Viral delivered gene therapy to treat catecholaminergic polymorphic ventricular tachycardia (CPVT2) in mouse models

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 (CASQ2(D307H)) or CASQ2 knockout (CASQ2(Delta/Delta)). Adeno-associated virus (AAV) particles containing the CASQ2 gene (AAV(CASQ2)) 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 CASQ2(Delta/Delta) mice injected intracardiacally with AAVCASQ2 expressed 40% +/- 25% of the normal CASQ2 protein level, which was increased compared to untreated CASQ2(Delta/Delta) mice (n 5 10; P,.05). Intraperitoneal therapy led to a significantly elevated expression of the CASQ2 protein, which was comparable in CASQ2(D307H) (n = 12) and CASQ2(Delta/Delta) (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 AAV(CASQ2) 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.