RATIONALE: Catecholaminergic polymorphic ventricular tachycardia is an inherited 
disease that predisposes to cardiac arrest and sudden death. The disease is 
associated with mutations in the genes encoding for the cardiac ryanodine 
receptor (RyR2) and cardiac calsequestrin (CASQ2). CASQ2 mutations lead to a 
major loss of CASQ2 monomers, possibly because of enhanced degradation of the 
mutant protein. The decrease of CASQ2 is associated with a reduction in the 
levels of Triadin (TrD) and Junctin (JnC), two proteins that form, with CASQ2 
and RyR2, a macromolecular complex devoted to control of calcium release from 
the sarcoplasmic reticulum.
OBJECTIVE: We intended to evaluate whether viral gene transfer of wild-type 
CASQ2 may rescue the broad spectrum of abnormalities caused by mutant CASQ2.
METHODS AND RESULTS: We used an adeno-associated serotype 9 viral vector to 
express a green fluorescent protein-tagged CASQ2 construct. Twenty weeks after 
intraperitoneal injection of the vector in neonate CASQ2 KO mice, we observed 
normalization of the levels of calsequestrin, triadin, and junctin, rescue of 
electrophysiological and ultrastructural abnormalities caused by CASQ2 ablation, 
and lack of life-threatening arrhythmias.
CONCLUSIONS: We have proven the concept that induction of CASQ2 expression in 
knockout mice reverts the molecular, structural, and electric abnormalities and 
prevents life-threatening arrhythmias in CASQ2-defective catecholaminergic 
polymorphic ventricular tachycardia mice. These data support the view that 
development of CASQ2 viral gene transfer could have clinical application.