A UC San Diego–led team used gene therapy to restore a key heart protein in models of arrhythmogenic cardiomyopathy, a major cause of sudden death in young athletes. The approach improved heart function, reduced arrhythmias and more than doubled survival in mice.
A gene therapy that restores a single, crucial heart protein has dramatically improved heart function and survival in mouse models of a deadly inherited heart disease that often strikes young athletes.
The work, led by researchers at the University of California San Diego School of Medicine, suggests that one gene-based treatment might eventually help many people with arrhythmogenic cardiomyopathy, or ACM, even though they carry different underlying mutations.
ACM is a genetic disease that weakens the heart’s pumping ability and is a leading cause of sudden cardiac death in young people. It disproportionately affects athletes, who may feel fit and strong while unknowingly living with a fragile heart.
“At first glance, you would think these individuals are very healthy as they are active and exercising regularly, but unfortunately they’re born with genetic mistakes that weaken the glue holding heart muscle cells together,” senior corresponding author Farah Sheikh, a professor of medicine at UC San Diego School of Medicine, said in a news release. “As those cells begin to fail, the heart becomes increasingly vulnerable to the stress of every heartbeat, which can lead to sudden death or over time, heart failure.”
In ACM, mutations occur in genes that encode desmosomes, the structures that act like rivets between heart muscle cells. When these rivets fail, cells pull apart under the constant mechanical stress of beating, die off and are gradually replaced by scar and fat. That scarring disrupts both the heart’s pumping power and its electrical signals, setting the stage for dangerous arrhythmias.
Sheikh’s group previously developed a gene therapy that targets the most common ACM mutation, in a desmosomal protein called plakophilin-2. That mutation-specific therapy is already in early-stage clinical trials. But ACM can be caused by mutations in several different desmosomal genes, and some of those genes are too large to fit into standard gene therapy delivery systems. That has left many patients without a clear path to treatment.
In the new study, published today in the journal Circulation: Heart Failure, the team took a different tack. Instead of fixing each faulty gene one by one, they focused on a shared weak point across many forms of ACM: loss of a protein called connexin-43.
Connexin-43 forms channels that allow electrical signals to pass quickly from one heart cell to the next, helping coordinate each heartbeat. It is often reduced or missing in ACM, but had not been shown to repair the heart’s mechanical structure.
Using a gene therapy vector to deliver a healthy version of the connexin-43 gene, the researchers treated mouse models of several inherited forms of ACM. The results were striking.
Restoring connexin-43 more than doubled the animals’ lifespan. It improved the heart’s ability to pump blood and prevented the heart from enlarging, a common sign of worsening disease. The therapy also led to a dramatic reduction in arrhythmias and improved electrical conduction through the heart.
Perhaps most surprising, the treatment appeared to repair the physical connections between heart cells. Desmosomal proteins that help keep muscle cells tightly linked were restored, and structural defects in heart tissue were corrected. These benefits were seen even when the therapy was given at advanced stages of disease, suggesting a potentially wide treatment window.
To see if the approach might translate to humans, the team tested it in heart muscle cells grown in the lab from induced pluripotent stem cells donated by ACM patients. As in the mice, boosting connexin-43 helped the cells stay intact, beat more regularly and regain key proteins needed for strong mechanical connections.
The researchers then dug deeper into how a protein best known for its role in electrical signaling could influence the heart’s structure. They found evidence that connexin-43 can move into the cell nucleus, where genetic instructions are stored and read.
“What surprised us was that connexin-43 moves into the nucleus,” Sheikh added. “That finding suggested it may help reprogram heart muscle cells to strengthen their mechanical connections and improve heart function. Connexin-43 might not just not be keeping the cell together electrically, but structurally as well.”
By influencing gene activity in the nucleus, connexin-43 appears to stimulate production of mechanical junction proteins that help glue heart cells together. That dual role — supporting both electrical and structural integrity — could make it a powerful target for therapy.
“We found that defects in these cellular connections could be corrected using connexin-43 gene therapy,” added Sheikh. “That gave us confidence that this approach may have broader therapeutic potential across multiple genetic forms of the disease, as it is known to be a common downstream defect. Conceptually, it offers a way to help glue heart muscle cells back together again, and we’re really encouraged by that.”
The connexin-43 program, which has been acquired by LEXEO Therapeutics, is currently in commercial development, according to Sheikh. Preclinical studies are underway to further evaluate safety, dosing and long-term effects before any human trials can begin.
Although the current work focused on ACM, the implications could extend beyond this one condition. Connexin-43 is often reduced in other types of cardiomyopathy and in heart failure, raising the possibility that a similar strategy might help a broader group of patients whose hearts are weakened by different causes.
“We want to understand how broadly this therapy can be applied across heart diseases and identify the window in which treatment has the greatest chance of having a positive outcome,” Sheikh added.
For now, the findings offer a hopeful glimpse of a future in which a single, carefully designed gene therapy might protect the hearts of people who never suspected they were at risk — including young athletes whose first symptom of ACM is too often their last.