Antisense Oligonucleotide Therapy for Calmodulinopathy

Calmodulinopathies are rare inherited arrhythmia syndromes caused by dominant heterozygous variants in , , or , 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. We tested this hypothesis using human induced pluripotent stem cell-derived cardiomyocyte and mouse models of pathogenic variants. Human 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 induced pluripotent stem cell-derived cardiomyocytes. Similarly, an ASO targeting murine depleted transcript without affecting CaM protein level. This ASO alleviated drug-induced bidirectional ventricular tachycardia in mice without a deleterious effect on cardiac electrical or contractile function. These results provide proof of concept that ASOs targeting individual calmodulin genes are potentially effective and safe therapies for calmodulinopathies.