C atecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening familial disorder characterized by adrenergically mediated arrhythmias in a structurally normal heart that may lead to sudden death.1 Two genetic forms of CPVT have been identified: the autosomal-dominant variant caused by mutations in the cardiac ryanodine receptor type 2 (RyR2) gene 2 and the autosomal-recessive variantBackground-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 CASQ2 R33Q/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. caused by mutations in the cardiac calsequestrin 2 (CASQ2) gene. 3 Additionally, 4 other genes have been associated with a clinical spectrum of manifestations consistent with the diagnosis of CPVT or with its phenocopies. [4][5][6] Interestingly, RyR2 and CASQ2 mutations induce diastolic Ca 2+ release from the sarcoplasmic reticulum (SR), leading to the development of delayed afterdepolarizations (DADs) and triggered activity (TA), which may precipitate life-threatening arrhythmias.7-10 This arrhythmogenic mechanism has been confirmed in patients during monophasic action potential recordings that documented the presence of adrenergically mediated DADs and TA in patients with CPVT. 11CPVT, unless promptly diagnosed and treated, may be lethal, as documented by the fact that up to 30% of untreated individuals die suddenly before the ...

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