Abstract:

Background — Catecholaminergic polymorphic ventricular tachycardia is an inherited arrhythmogenic disorder characterized by sudden cardiac death in children. Drug therapy is still insufficient to provide full protection against cardiac arrest, and the use of implantable defibrillators in the pediatric population is limited by side effects. There is therefore a need to explore the curative potential of gene therapy for this disease. We investigated the efficacy and durability of viral gene transfer of the calsequestrin 2 (CASQ2) wild-type gene in a catecholaminergic polymorphic ventricular tachycardia knock-in mouse model carrying the CASQ2R33Q/R33Q (R33Q) mutation. Methods and Results — We engineered an adeno-associated viral vector serotype 9 (AAV9) containing cDNA of CASQ2 wild-type (AAV9-CASQ2) plus the green fluorescent protein (GFP) gene to infect newborn R33Q mice studied by in vivo and in vitro protocols at 6, 9, and 12 months to investigate the ability of the infection to prevent the disease and adult R33Q mice studied after 2 months to assess whether the AAV9-CASQ2 delivery could revert the catecholaminergic polymorphic ventricular tachycardia phenotype. In both protocols, we observed the restoration of physiological expression and interaction of CASQ2, junctin, and triadin; the rescue of electrophysiological and ultrastructural abnormalities in calcium release units present in R33Q mice; and the lack of life-threatening arrhythmias. Conclusions — Our data demonstrate that viral gene transfer of wild-type CASQ2 into the heart of R33Q mice prevents and reverts severe manifestations of catecholaminergic polymorphic ventricular tachycardia and that this curative effect lasts for 1 year after a single injection of the vector, thus posing the rationale for the design of a clinical trial.

Author affiliation: Denegri, Marco. Fondazione Salvatore Maugeri; Italia

Author affiliation: Bongianino, Rossana. Fondazione Salvatore Maugeri; Italia

Author affiliation: Lodola, Francesco. Fondazione Salvatore Maugeri; Italia

Author affiliation: Boncompagni, Simona. University G. d’Annunzio; Italia

Author affiliation: de Giusti, Verónica Celeste. Fondazione Salvatore Maugeri; Italia. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico la Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; Argentina

Author affiliation: Avelino Cruz, José E.. Fondazione Salvatore Maugeri; Italia. Benemerita Universidad Autonoma de Puebla; México

Author affiliation: Liu, Nian. Capital Medical University; China

Author affiliation: Persampieri, Simone. Fondazione Salvatore Maugeri; Italia

Author affiliation: Curcio, Antonio. Fondazione Salvatore Maugeri; Italia. University of Magna Graecia; Italia

Author affiliation: Esposito, Francesca. Fondazione Salvatore Maugeri; Italia. Università Degli Studi Di Napoli Federico Ii; Italia

Author affiliation: Pietrangelo, Laura. University G. d’Annunzio; Italia

Author affiliation: Marty, Isabelle. Grenoble Institut des Neurosciences; Francia. Universite Joseph Fourier; Francia

Author affiliation: Villani, Laura. Fondazione Salvatore Maugeri; Italia

Author affiliation: Moyaho, Alejandro. Benemerita Universidad Autonoma de Puebla; México

Author affiliation: Baiardi, Paola. Fondazione Salvatore Maugeri; Italia

Author affiliation: Auricchio, Alberto. Telethon Institute of Genetics and Medicine; Italia. Università Degli Studi Di Napoli Federico Ii; Italia

Author affiliation: Protasi, Feliciano. University G. d’Annunzio; Italia

Author affiliation: Napolitano, Carlo. Fondazione Salvatore Maugeri; Italia

Author affiliation: Priori, Silvia G.. Fondazione Salvatore Maugeri; Italia. University of Pavia; Italia