Exploring the therapeutic potential of calmodulin in the context of inherited cardiac arrhythmia

Long QT Syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are congenital cardiac disorders that can affect children. Symptoms include fainting, seizures and can lead to life-threatening arrhythmia. Human genetic mutations in the ubiquitous calcium sensor calmodulin (CaM) have been identified in patients living with LQTS and CPVT, suggesting a key role of CaM in the molecular aetiology of the diseases. Current management often involving beta-blockers or implantable devices present significant limitations and side effects. Beta-blockers can cause fatigue, dizziness and not all patients respond optimally. Implantable devices carry a significant risk of infection and device-related complications. Therefore, there is an imperative need to explore alternative therapeutic strategies. In CaM-associated LQTS and CPVT syndromes, CaM’s ability to sense calcium, and interact with and regulate ion channels relevant to cardiac muscle contraction is impaired. In this project, we will develop, characterise and validate hypersensitive CaM variants (CaM HS) with improved calcium binding properties and the ability to restore ion channel regulation, as a novel therapeutic avenue. With recent promising advances in protein replacement therapy, our findings will reveal the therapeutic potential of CaM in the context of inherited cardiac arrhythmia.