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.
References
Original article
Bezzerides, V. J. et al. Gene therapy for catecholaminergic polymorphic ventricular tachycardia by inhibition of Ca2+/calmodulin-dependent kinase II. Circulation https://doi.org/10.1161/CIRCULATIONAHA.118.038514 (2019)
Further reading
Bongianino, R. & Priori, S. G. Gene therapy to treat cardiac arrhythmias. Nat. Rev. Cardiol. 12, 531–546 (2015)
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Lim, G.B. Gene therapy to inhibit CaMKII in CPVT. Nat Rev Cardiol 16, 456 (2019). https://doi.org/10.1038/s41569-019-0226-x
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DOI: https://doi.org/10.1038/s41569-019-0226-x