Researchers in Australia have developed a gene therapy that could restore heart function in children born with mutations that cause cardiomyopathy. A study published in Nature Cardiovascular Research suggests this approach could potentially address more than 25% of cardiomyopathies that have a genetic basis.
Cardiomyopathy encompasses a group of diseases that impair the heart’s ability to pump blood. These conditions cause the heart to become enlarged, with weak and irregular heartbeats, increasing the risk of heart failure. Although cardiomyopathy affects around 30 million people worldwide, treatment options remain limited and are often highly invasive.
“Genetic forms of cardiomyopathy are a major reason why children need heart transplants,” said James McNamara, PhD, honorary fellow and team leader at Murdoch Children’s Research Institute (MCRI). “If this success translates to patients, the gene therapy could become the first targeted treatment for a range of inherited heart diseases, offering families a future without progressive heart failure or the eventual need for a transplant.”
“Additionally, this would spare children from invasive surgical or catheter-based procedures, long-term medication, and needing implantable devices like pacemakers and defibrillators to repair or manage their heart defect.”
The gene therapy is designed to deliver a healthy copy of the ALPK3 gene, which plays an important role in the development and maintenance of muscle tissue. Variants in ALPK3 can cause severe cardiomyopathy, with affected children often requiring lifelong medication, repeated surgical procedures, and, when the disease progresses, heart transplantation.
McNamara’s team first developed a mouse model of ALPK3 that replicated the early-onset and severity seen in children with the same mutations. In these mice, the gene therapy successfully repaired the structural abnormalities in diseased heart cells and restored pumping function to their failing hearts.
“Strikingly, we also showed that the therapy not only prevented cardiomyopathy in newborn mice but also completely reversed the disease in adult mice,” said McNamara. “This was a huge result, suggesting to us that the heart heavily depends on ALPK3.”
The researchers then recreated the disease in human heart organoids grown from patient stem cells. Treatment with the gene therapy successfully restored their contractile function.
“These mini hearts in a dish had the same type of cardiomyopathy as the patients with ALPK3 gene variants,” said McNamara. “We replaced the faulty copies of ALPK3 with the healthy version and completely restored normal beat strength and rhythm in the mini hearts.”
Next, the scientists investigated whether the gene therapy could be used to target other genetic forms of cardiomyopathy. Using Geneformer, an AI model developed by collaborators at Gladstone Institutes, they predicted that patients with mutations in the MYH7 and TTN genes were likely to benefit from this treatment—with TTN variants alone accounting for up to a quarter of all cases of dilated cardiomyopathy.
“Importantly, the TTN gene itself is just too big to replace using our current gene therapy technologies, so this gene therapy could be used to treat a range of cardiomyopathies, including those with no current treatments,” said McNamara. “Variations in TTN are the most common genetic cause of dilated cardiomyopathy, so this therapy could really address a large unmet need for patients worldwide.”
The broader potential of the gene therapy remains to be explored, including experimental confirmation of which of the predicted MYH7 and TTN variants can be treated with this approach and to what extent.
“Further safety studies are needed before we start human trials, but we have been blown away by the preclinical results,” said Enzo Porrello, PhD, professor at MCRI and director of the Melbourne node of the Novo Nordisk Foundation Centre for Stem Cell Medicine. “We are now seeking commercial partners to take this gene therapy into human clinical trials.”
