Research led by the University of California San Diego shows good preclinical outcomes for an adeno-associated-viral (AAV) vector gene therapy for treatment of the genetic heart disease arrhythmogenic cardiomyopathy.
The therapy acts by replacing connexin‑43, a protein present in low quantities in people with this condition. Connexin‑43 is crucial for preserving electrical conduction in heart muscle and restoring normal rhythm, but it had not previously been implicated in directly repairing the heart muscle.
The therapy was originally developed by Stelios Therapeutics, which was acquired by gene therapy biotech Lexeo Therapeutics in 2021. Lexeo is now developing it further along with other therapies for similar rare genetic heart conditions.
Arrhythmogenic cardiomyopathy affects as many as 70,000 people in the U.S. and is a genetic heart‑muscle disease in which cardiac muscle cells gradually die to be replaced by fibrous and fatty tissue, particularly in the ventricles of the 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,” said lead investigator Farah Sheikh, PhD, professor of medicine at UC San Diego School of Medicine and co-founder of Stelios Therapeutics, in a press statement.
“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.”
The current study, published in Circulation: Heart Failure, was carried out in mouse models and human cell lines. The team found that restoring connexin-43 more than doubled the lifespan of the model mice. It also improved the ability of the animal’s hearts to pump blood around their bodies and reduced signs of heart enlargement. The researchers also found lower levels of heart arrhythmias and electrical conduction problems and the treatment also seemed to improve heart structure in the model animals.
Notably, the improvements seen in the study were also seen in animals with a more advanced form of the condition where heart damage had already occurred.
In human heart cell lines the researchers saw similar results to in the model mice with more intact cells that were able to beat normally. These cells also had higher levels of the proteins needed for healthy hearts after the treatment.
Lexeo is now working on how best to develop this program further and bring it into the clinic. “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.
