Antisense Oligonucleotide Therapy for Calmodulinopathy

• DOI: 10.1161/circulationaha.123.068111
• Publication Date: 2024-08-19T09:00:33Z
• Authors: Raul H. Bortolin; Farina Nawar; Chaehyoung Park; Michael A. Trembley; Maksymilian Prond...; Mason E. Sweat; Peizhe Wang; Jiehui Chen; Fujian Lu; Carter Liou; Paul Berkson; Erin M. Keating; Daisuke Yoshinaga; Nikoleta Pavlaki; Thomas Samenuk; Cecilia B. Cavazzoni; Peter T. Sage; Qing Ma; Robert D. Whitehill; Dominic J. Abrams; Chrystalle Katte ...; Juan Putra; Sanda Alexandrescu; Shuai Guo; Wen-Chin Tsai; Michael Rubart; Dieter A. Kubli; Adam E. Mullick; Vassilios J. Bezz...; William T. Pu
• Keywords: Mice, Knockout; Induced Pluripotent Stem Cells; Action Potentials; Genetic Therapy; Oligonucleotides, Antisense; Mice; Long QT Syndrome; Disease Models, Animal; 03 medical and health sciences; 0302 clinical medicine; Calmodulin; Animals; Humans; Myocytes, Cardiac

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.