ACM is a genetic heart disease primarily characterized by myocardial cell loss and the replacement of heart muscle with fibrotic tissue and fatty deposits.
ACM can result from pathogenic mutations in several desmosomal genes. These genetic pathogenic variants impair the structure and function of cardiac desmosomes, which are membrane protein complexes engaged in cell-to-cell adhesion and the structural integrity of the ventricular myocardium. Lack of functioning cardiac desmosomes can lead to rhythm abnormalities, fibrosis, myocardial cell death, heart dysfunction, and sudden cardiac death.
ACM has an estimated prevalence of approximately 130,000 in the United States, with more than half of those individuals estimated to have a genetic form of the disease. We believe that five desmosomal genes account for nearly all genetic cases of ACM. Pathogenic variants in the plakophilin-2 (PKP2) gene are the most commonly known genetic cause of ACM, with an estimated prevalence of 60,000 individuals in the US.
No approved disease-modifying treatments for ACM exist, and thus, strategies targeted at elevating PKP2 protein levels represent a potential avenue to treat a large portion of ACM populations.
