AAV9-mediated gene supplementation therapy prevents and rescues arrhythmogenic cardiomyopathy in Pnpla2-mutated mice.

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder involving ventricular arrhythmias, cardiac dysfunction, and fibrofatty myocardial replacement. Current treatments are largely palliative, with heart transplantation as the only definitive option for advanced ACM. Here, we show that, building upon our previous identification of a patient with a PNPLA2(c.G245A/c.G245A) mutation, we developed a murine model carrying the same mutation, faithfully mimicking key ACM phenotypes such as arrhythmias, lipid accumulation, and fibrosis. Using an adeno-associated virus 9 (AAV9) vector to deliver the human PNPLA2 gene, we demonstrated that early intervention prevented ACM onset, while later treatment reversed established symptoms and extended survival. Treated mice exhibited improved cardiac function, lipid metabolism, and normalized fatty acid pathways, verified by single-nucleus sequencing. These findings highlight the promise of AAV9-mediated PNPLA2 gene supplementation as an effective therapeutic strategy for ACM, supporting further clinical exploration.