TY - JOUR
T1 - Viral delivered gene therapy to treat catecholaminergic polymorphic ventricular tachycardia (CPVT2) in mouse models
AU - Kurtzwald-Josefson, Efrat
AU - Yadin, Dor
AU - Harun-Khun, Shiraz
AU - Waldman, Maayan
AU - Aravot, Dan
AU - Shainberg, Asher
AU - Eldar, Michael
AU - Hochhauser, Edith
AU - Arad, Michael
N1 - Publisher Copyright:
© 2017 Heart Rhythm Society
PY - 2017/7
Y1 - 2017/7
N2 - 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.
AB - 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.
KW - Adeno-associated virus
KW - CPVT
KW - Calsequestrin
KW - Gene therapy
KW - Ventricular arrhythmia
UR - http://www.scopus.com/inward/record.url?scp=85019922023&partnerID=8YFLogxK
U2 - 10.1016/j.hrthm.2017.03.025
DO - 10.1016/j.hrthm.2017.03.025
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C2 - 28336343
AN - SCOPUS:85019922023
SN - 1547-5271
VL - 14
SP - 1053
EP - 1060
JO - Heart Rhythm
JF - Heart Rhythm
IS - 7
ER -