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 Calm1 ^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.
Competing Interests: A.E.M. and D.K. are employees of Ionis Pharmaceuticals, which provided the ASOs used in this study. The other authors report no conflicts.