A single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by Catecholaminergic Polymorphic Ventricular Tachycardia is able to cure the disease from birth to advanced age.

MARCO DENEGRI; BONGIANINO R; LODOLA F; BONCOMPAGNI S; DE GIUSTI VC; AVELINO CRUZ JE; LIU NIAN; CURCIO A; LAURA PIETRANGELO; AURICCHIO A; LAURA VILLANI; PERSAMPIERI S; PROTASI F; NAPOLITANO C; PRIORI SG

CIRCULATION

LIPPINCOTT WILLIAMS & WILKINS

Lugar: Philadelphia; Año: 2014 vol. 129 p. 2673 - 2681

0009-7322

Rationale: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by sudden cardiac death in children. Drug therapy is still insufficient to provide full protection from cardiac arrest and the use of the implantable defibrillator in the pediatric population is limited by side effects. There is therefore a rational to explore the curative potential of gene therapy for this disease. Objective: We investigated the efficacy and durability of viral gene transfer of CASQ2 wild type gene in a CPVT mice 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 GFP to infect: 1) 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; 2) adult R33Q mice studied after 2 months to assess if the AAV9-CASQ2 delivery could revert the CPVT phenotype. In both protocols we observed the restoration of physiological expression and interaction of Calsequestrin, Junctin and Triadin, the rescue of electrophysiological and ultrastructural abnormalities 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 CPVT and this curative effect lasts for one year after a single injection of the vector thus posing the rationale for the design of a clinical trial.