Cardiomyocyte-selective gene therapy to inhibit Ca2+/calmodulin-dependent protein kinase II (CaMKII) effectively suppresses ventricular arrhythmias in mice with mutations known to cause catecholaminergic polymorphic ventricular tachycardia (CPVT). “Delivery of a CaMKII inhibitory peptide by adeno-associated virus (AAV) represents a novel single-dose gene therapy for CPVT,” summarize the researchers.

A characteristic feature of CPVT is adrenergically triggered arrhythmias. Inhibition of CaMKII, an adrenergically activated kinase, has been identified as a therapeutic approach for CPVT. However, given that CaMKII is essential for brain function, CaMKII must be selectively inhibited in cardiomyocytes. Therefore, the researchers designed an AAV vector containing a potent CaMKII inhibitory peptide (AIP) fused to green fluorescent protein (GFP) and expressed from a cardiomyocyte-selective promoter (AAV9–AIP–GFP).

Systemic delivery of AAV9–AIP–GFP to neonatal mice with a CPVT-causing mutation (RyrR176Q/+) resulted in robust expression in the heart, without substantial expression in extracardiac tissues. Ventricular arrhythmias induced by either programmed ventricular pacing or β-adrenergic stimulation were suppressed. Similar results were obtained in adolescent mice with a CPVT-causing mutation.

Of note, when a cell-permeable form of AIP was delivered directly to human induced pluripotent stem cell-derived cardiomyocytes derived from two patients with different combinations of CPVT-associated amino acid substitutions in RYR2 (one with S404R and N658S and the other with G3946S and G1885E), abnormal Ca2+-release events were suppressed. “CaMKII inhibition is a potentially translatable and effective therapy for CPVT patients with diverse RYR2 mutations,” conclude the investigators.