Antisense Oligonucleotide Therapy for Calmodulinopathy.

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Medicine

Background:

• Calmodulinopathies are rare inherited arrhythmia syndromes.
• These conditions stem from dominant heterozygous variants in CALM1, CALM2, or CALM3 genes, which encode the calmodulin (CaM) protein.
• The identical nature of CaM protein across these genes presents a therapeutic challenge.

Purpose of the Study:

• To test the hypothesis that antisense oligonucleotide (ASO)-mediated depletion of an affected calmodulin gene could ameliorate disease manifestations.
• To determine if other calmodulin genes could preserve CaM levels and function during targeted depletion.
• To explore ASOs as a potential therapeutic strategy for calmodulinopathies.

Main Methods:

• Utilized human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and mouse models harboring CALM1 pathogenic variants.
• Administered ASOs targeting CALM1 in hiPSC-CMs and murine Calm1 in mice.
• Assessed effects on action potential duration, repolarization, CaM protein levels, transcript levels, and cardiac electrical and contractile function.

Main Results:

• Human CALM1-variant hiPSC-CMs exhibited prolonged action potentials, modeling congenital long QT syndrome.
• CALM1-depleting ASOs normalized repolarization in affected hiPSC-CMs without altering CaM protein levels.
• ASO targeting murine Calm1 depleted Calm1 transcript, alleviated drug-induced ventricular tachycardia in mice, and did not impair cardiac function.

Conclusions:

• Demonstrated proof of concept for ASO-mediated therapy in calmodulinopathies.
• ASOs targeting individual calmodulin genes are potentially effective treatments.
• This therapeutic strategy appears safe, preserving overall CaM levels and cardiac function.