PROJECT SUMMARY/ABSTRACT Arrhythmogenic cardiomyopathy (ACM) is a devastating inherited disease that causes sudden cardiac death in young people, accounting for up to 22% of sudden cardiac deaths in adults under 35. Despite the identification of causative mutations, the mechanisms triggering ACM remain elusive, and there are no preventative therapies for individuals carrying pathogenic allele variants. This project aims to elucidate the role of early immune cell infiltration in the development of ACM using a mouse model with a mutation in the desmosomal protein desmoglein-2 (DSG2). The central hypothesis is that early myocardial immune cell populations and inflammation determine ACM phenotype severity. Aim 1 will test whether increased neonatal immune cell recruitment accelerates arrhythmias, scar formation, and death in DSG2 mice using an adeno-associated viral vector expressing a modified COVID-19 spike protein. Aim 2 will investigate if neonatal treatment with gene therapy expressing the connexin-43 isoform GJA1-20k reduces immune cell burden, inflammation, arrhythmias, and death. Aim 3 will examine whether neonatal inhibition of NFκB signaling using AAV9-A20 can prevent immune cell recruitment, inflammation, arrhythmias, and scarring. This research is significant because it explores a novel preventative treatment strategy for ACM, focusing on early immune-mediated events that precede overt cardiac dysfunction. The approach is innovative in its examination of the early stages of ACM pathophysiology and the use of gene therapies targeting different pathways involved in disease development. The expected outcomes include identifying the role of immune cell infiltration in ACM, demonstrating the efficacy of two gene therapies, and offering a new treatment paradigm focusing on early intervention to prevent disease onset in genetically susceptible individuals. If successful, this work could transform the clinical management of ACM and potentially other genetic cardiomyopathies.

Arrhythmogenic cardiomyopathy (ACM) is an inherited disease that causes sudden cardiac death in young people, but there are no cures or preventative treatments for those carrying disease-causing mutations. Using a mouse model, this study will test whether reducing inflammation and immune cell infiltration in the heart muscle can prevent the onset of the deadly complications of ACM. If successful, this research could lead to the first preventative therapy for ACM that could be administered in childhood to spare mutation carriers from ever developing this devastating disease.