UC San Diego Study Reveals “Universal” AAV Gene Therapy Could Halt Sudden Cardiac Death in Arrhythmogenic Cardiomyopathy

January 26, 2026 — Researchers at the University of California San Diego have unveiled a breakthrough AAV-mediated approach that could provide a mutation-independent cure for Arrhythmogenic Cardiomyopathy (ACM), a leading cause of sudden death in young athletes. The study, published today in Circulation: Heart Failure, demonstrates that an AAV gene therapy designed to restore a single protein, connexin-43, can repair heart structure and dramatically extend survival across multiple genetic forms of the disease.

Arrhythmogenic Cardiomyopathy (ACM) is traditionally viewed as a “disease of the glue,” where genetic mutations weaken the desmosomes that hold heart cells together. While previous efforts focused on AAV gene therapy targeting specific mutations like plakophilin-2—a strategy currently in Phase 1/2 trials—many other ACM mutations involve genes too large to fit inside standard AAV vector delivery systems. By pivoting to connexin-43, a protein that is universally deficient in ACM patients regardless of their specific mutation, the team has identified a way to use a compact AAV delivery vehicle to treat a much broader patient population.

The research team, led by Professor Farah Sheikh, utilized a specialized AAV gene therapy to deliver connexin-43 into mouse models suffering from advanced heart failure. The results were unprecedented: the AAV-delivered protein more than doubled the subjects’ lifespan, reduced life-threatening arrhythmias, and effectively “glued” the heart cells back together. Even in late-stage disease, the AAV treatment corrected structural defects and prevented the heart from enlarging, suggesting that AAV-based intervention remains viable even after significant damage has occurred.

“What surprised us was that connexin-43 moves into the nucleus,” said Sheikh. “This suggests the AAV-transduced protein may help reprogram heart muscle cells to strengthen mechanical connections. It isn’t just keeping the cell together electrically, but structurally as well.” The team validated these findings using human iPSC-derived heart cells from ACM patients, where the AAV gene therapy successfully restored cellular integrity and normal beating patterns.

This AAV program has already moved into commercial development after being acquired by LEXEO Therapeutics. As preclinical safety evaluations continue, the team believes this AAV-based strategy could eventually be applied to other forms of heart failure where connexin-43 is similarly missing. By moving away from “one-off” mutation repairs toward a universal AAV corrective, the researchers hope to provide a definitive shield against the sudden cardiac stress that currently claims the lives of many young, seemingly healthy individuals.