Antisense Oligonucleotide Therapy for Calmodulinopathy

BACKGROUND: Calmodulinopathies are rare inherited arrhythmia syndromes caused by dominant heterozygous variants in CALM1 , CALM2 , or CALM3 , which each encode the identical CaM (calmodulin) protein. We hypothesized that antisense oligonucleotide (ASO)–mediated depletion of an affected calmodulin gene would ameliorate disease manifestations, whereas the other 2 calmodulin genes would preserve CaM level and function. METHODS: We tested this hypothesis using human induced pluripotent stem cell–derived cardiomyocyte and mouse models of CALM1 pathogenic variants. RESULTS: Human CALM1 F142L/+ induced pluripotent stem cell–derived cardiomyocytes exhibited prolonged action potentials, modeling congenital long QT syndrome. CALM1 knockout or CALM1-depleting ASOs did not alter CaM protein level and normalized repolarization duration of CALM1 F142L/+ induced pluripotent stem cell–derived cardiomyocytes. Similarly, an ASO targeting murine Calm1 depleted Calm1 transcript without affecting CaM protein level. This ASO alleviated drug-induced bidirectional ventricular tachycardia in Calm N98S/+ mice without a deleterious effect on cardiac electrical or contractile function. CONCLUSIONS: These results provide proof of concept that ASOs targeting individual calmodulin genes are potentially effective and safe therapies for calmodulinopathies.