Antisense Oligonucleotide Therapy for Calmodulinopathy.

Abstract

Calmodulinopathies are rare inherited arrhythmia syndromes caused by dominant heterozygous variants in <i>CALM1</i>, <i>CALM2</i>, or <i>CALM3</i>, 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 <i>CALM1</i> pathogenic variants. Human <i>CALM1</i>^{<i>F142L/+</i>} 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 <i>CALM1</i>^{<i>F142L/+</i>} induced pluripotent stem cell-derived cardiomyocytes. Similarly, an ASO targeting murine <i>Calm1</i> depleted <i>Calm1</i> transcript without affecting CaM protein level. This ASO alleviated drug-induced bidirectional ventricular tachycardia in <i>Calm1</i>^{<i>N98S/+</i>} 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.