Melbourne researchers have made a gene therapy breakthrough that could restore heart function in children with genetic heart disease, sparing them the need for transplants.
The world-first study, led by Murdoch Children’s Research Institute (MCRI) and published in Nature Cardiovascular Research , found delivering a healthy copy of the ALPK3 gene in a single injection reversed heart muscle disease in lab-grown patient heart tissue and mouse models.
Variants in the ALPK3 gene can cause cardiomyopathy, a group of diseases that affect the heart’s ability to pump blood around the body, leading to enlarged hearts with weak and irregular heartbeats. Patients with cardiomyopathy, affecting about 30 million people, are at greater risk of heart failure and death and treatment options are limited.
Remarkably, the study also found the gene therapy might help correct other genetic heart diseases, not just ones caused by ALPK3 variants, such as those impacted by the MYH7 gene and TTN truncating variants (TTNtv), the most common genetic cause of dilated cardiomyopathy.
MCRI Dr James McNamara said the findings were the first big step towards a cure for genetic heart disease.
“Heart disease is the leading cause of death worldwide and genetic forms of cardiomyopathy are a major reason why children need heart transplants,” he said. “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 defibrators to repair or manage their heart defect.”
For the study, the research team first created a pre‑clinical mouse model of ALPK3 cardiomyopathy. Newborn animals carrying a faulty version of ALPK3 develop enlarged hearts and reduced cardiac function, closely mirroring the early-onset severity seen in affected children.
“By adding back the healthy version of ALPK3 using our candidate gene therapy, we repaired the structural scaffolding of the diseased heart cells and revived the pumping power of the failing hearts,” Dr McNamara said.
“Strikingly, we also showed that the therapy not only prevented cardiomyopathy in newborn mice but also completely reversed the disease in adult mice. This was a huge result, suggesting to us that the heart heavily depends on ALPK3.”
Dr McNamara said the team then extended their findings by recreating the disease in heart tissues grown from stem cells created from patients with the same genetic ALPK3 variation used in the mice.
“These mini hearts in a dish had the same type of cardiomyopathy as the patients with ALPK3 gene variants,” he said. “We replaced the faulty copies of ALPK3 with the healthy version and completely restored normal beat strength and rhythm in the mini hearts.”
The team then used Geneformer, an artificial intelligence tool developed by collaborator Assistant Professor Christina Theodoris at Gladstone Institutes in California, to test whether hypothetical disease-causing variants in other genes could also be rescued by restoring the ALPK3 protein.
The model predicted that ALPK3 was most strongly linked to Titin (TTN). TTN-truncating variants (TTNtv), accounting for up to one quarter of all dilated cardiomyopathy cases, have very limited therapeutic options.
“With ALPK3 acting like a quality control switch for many major heart proteins, we wanted to test if supplying extra copies of the healthy gene could ensure all parts of the machinery function correctly, even in other types of genetic heart disease,” Dr McNamara said. “We have found that adding healthy ALPK3 improved muscle contraction in heart tissues made from people carrying truncated Titin.
“Importantly, the Titin 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. Variations in TTNtv are the most common genetic cause of dilated cardiomyopathy, so this therapy could really address a large unmet need for patients worldwide.”
MCRI Professor Enzo Porrello , also Director of the Melbourne node of the Novo Nordisk Foundation Centre for Stem Cell Medicine (reNEW) , said the results mirrored the field’s broader shift towards precision medicine in cardiology.
“Further safety studies are needed before we start human trials, but we have been blown away by the preclinical results,” he said. “We are now seeking commercial partners to take this gene therapy into human clinical trials.”
Kate, 9, has hypertrophic cardiomyopathy (HCM), caused by a variant in the MYH7 gene.
The condition causes the heart muscle to thicken, making it harder to pump blood, often causing shortness of breath, chest pain, dizziness and fainting, and is the leading cause of sudden cardiac death in young people.
Her mum Carly said shortly after giving birth a heart murmur was detected by their paediatrician. Further genetic testing confirmed Kate’s diagnosis and in the months that followed her condition deteriorated. Kate met her early milestones, but would sleep often, wasn’t gaining weight and had a blue tinge to her skin.
To alleviate the symptoms, Kate began treatment at The Royal Children’s Hospital (RCH).
“Once Kate started medications, she never showed signs of HCM, allowing her to live a relatively normal life,” Carly said. “Kate was still an energetic little girl who loved craft, ballet and swimming lessons. But with her heart being under so much pressure we knew she would eventually need surgery.”
Aged just three, Kate underwent open-heart surgery. Over eight hours, Kate’s surgical team at the RCH removed a small portion of her thickened heart muscle. Relieving this obstruction in the left ventricle, helps to improve blood flow, effectively treating symptoms like chest pain and fainting.
Carly said Kate had made an incredible recovery and no longer needed medications and any restrictions on physical activity.
She said the latest MCRI discovery was remarkable, with her family incredibly grateful that a team of scientists were dedicated to finding better treatments. The family recently visited the MCRI stem cell medicine lab to meet the team behind the breakthrough.
“Before Kate reaches high school, she will need to have a heart defibrillator implanted as her surgery isn’t a cure,” Carly said. “We hope that with the advances in medicine that someday there will be a cure for HCM. But in the meantime, we’re focussing on raising our little girl to be as happy and healthy as possible and we are committed to educating others about her condition.”
Researchers from The Royal Children’s Hospital, University of Melbourne, Monash University, Dynomics Inc, Queensland University of Technology and QIMR Berghofer also contributed to the findings.
Publication: James W. McNamara, Ellen B. Keen, Rebecca Sutton, Yinghan She, Hannah Huckstep, Lina H. H. Le, Neda R. Mehdiabadi, Madhavan S. Venkatesh, Brendan Griffen, Richard J. Mills, Christina V. Theodoris, James E. Hudson, Drew M. Titmarsh, Sean J. Humphrey, Enzo R. Porrello and David A. Elliott. ‘Alpha Protein Kinase 3 Gene Therapy Restores Heart Function in Mouse and Human Models of Cardiomyopathy,’ Nature Cardiovascular Research . DOI: 10.1038/s44161-026-00843-1
*The content of this communication is the sole responsibility of MCRI and does not reflect the views of the NHMRC.
Available for interview:
Dr James McNamara, MCRI Team Leader, Heart Disease
Professor David Elliott, MCRI Group Leader, Heart Disease
Carly, whose daughter Kate, 9, has hypertrophic cardiomyopathy
Nature Cardiovascular Research
Experimental study
Animals
Alpha Protein Kinase 3 Gene Therapy Restores Heart Function in Mouse and Human Models of Cardiomyopathy
19-Aug-2026