Could gene therapy treat a deadly heart condition that targets young athletes?

(Press-News.org) University of California San Diego-led team has discovered that restoring a key cardiac protein called connexin‑43 in a mouse model can dramatically improve heart function and extend survival in several inherited forms of arrhythmogenic cardiomyopathy (ACM). The research suggests that a single gene therapy might someday help a wide range of ACM patients, regardless of the specific mutation they carry. The study was published on January 26, 2026 in Circulation: Heart Failure.

ACM impedes the heart from pumping blood to the rest of the body, and is a leading cause of sudden cardiac death in young people. The condition disproportionately affects athletes, who may push their hearts to the limit during intense exercise, unaware that they have the condition.

“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,” said senior corresponding author Farah Sheikh, professor of medicine at UC San Diego School of Medicine. Over time, these weakened cells are replaced by scar tissue. “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.”

ACM is caused by mutations to genes that encode desmosomes — proteins that anchor heart cells to each other. Previous research by Sheikh and her colleagues led to the development of a gene therapy targeting the most common genetic mutation of ACM, plakophilin-2, which is currently being evaluated in Phase 1 / 2 clinical trials. However, ACM can arise from mutations in multiple desmosomal genes, some of which are too large for current gene therapy approaches, leaving a critical unmet need for therapeutic strategies that can address disease mechanisms across this broader patient population.

In the current study, instead of trying to repair the gene mutation specific to each form of ACM, the researchers focused on restoring connexin‑43, a protein often lacking in patients with all forms of the condition. Connexin-43 is essential for maintaining electrical conductivity in heart muscle and for reestablishing heart rhythm, but hasn’t previously been shown to repair muscle tissue itself.

Co-first author Jing Zhang, PhD, corresponding author Farah Sheikh, PhD and co-first author Matthew Ellis. Not pictured: co-first author Fabian Zanella, PhD. (Kyle Dykes/UC San Diego Health Sciences)

The researchers found that using gene therapy to restore connexin-43 in mouse models of arrhythmogenic cardiomyopathy:

More than doubled their lifespan Improved the heart’s ability to pump blood, and prevented enlargement of the heart Led to a dramatic reduction in heart arrhythmias and greater electrical conductivity Restored desmosome proteins that keep muscle cells connected to each other and corrected structural defects in heart tissue What’s more, these outcomes were even observed in mice who received gene therapy in advanced stages of the disease.

The team also tested the approach in human heart muscle cells derived from induced pluripotent stem cells provided by ACM patients. Similar to the mouse model, restoring connexin‑43 helped the heart cells stay intact, beat more normally, and regain the proteins needed for strong connections.

The researchers also found evidence that connexin‑43 may influence gene transcription inside the nucleus of cells, stimulating the production of key mechanical junction proteins.

“What surprised us was that connexin-43 moves into the nucleus,” said Sheikh. “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.”

This discovery could have major implications for the treatment of ACM.

Desmoplakin knockout mouse heart muscle section (left); connexin-43 treated mouse heart muscle section (right). (UC San Diego Health Sciences)

"We found that defects in these cellular connections could be corrected using connexin-43 gene therapy,” said 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 has been acquired by LEXEO Therapeutics and is now in commercial development, Sheikh said. Preclinical studies are underway to further evaluate safety and therapeutic potential.

Connexin-43 is often missing in the heart muscle cells of patients with other forms of cardiomyopathy and heart failure, according to Sheikh, opening up the possibility that this gene-based therapy could one day be applicable to a range of heart diseases.

“ 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,” said Sheikh.

Additional co-authors on the study include: Jing Zhang, Fabian Zanella, Matthew W. Ellis, William H. Bradford, Erika Joana Gutierrez‑Lara, Tsui‑Min Wang, Kyohei Fujita, Charlize Duron, Ioannis Karakikes, Robert C. Lyon, Valeria Mezzano, Cassiano Carromeu, Yusu Gu, Alysson R. Muotri and Kirk L. Peterson, University of California San Diego; Ioannis Karakikes, Stanford University School of Medicine and Stanford Cardiovascular Institute; Jason D. Roberts, Population Health Research Institute at Hamilton Health Sciences and McMaster University; Jody L. Martin, University of Illinois Chicago and Melvin M. Scheinman, University of California San Francisco.

The study was funded in part by the National Institutes of Health (grants HL162369, HL181001, F32HL172624 and 5K12GM068524), the California Institute of Regenerative Medicine (grant RB3‑05103) and the U.S. Department of Defense (grant W81XWH1810380).

Disclosures: Sheikh co-founded Stelios Therapeutics (acquired by LEXEO Therapeutics), is a co-founder and has an equity interest in Papillon Therapeutics and MyoTherapeutix and is a consultant for LEXEO Therapeutics.

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