Gene therapy restores heart function in mice and human heart organoids

Gene therapy designed to deliver a healthy copy of the ALPK3 gene can restore heart function, raising the possibility of a future treatment for some forms of inherited cardiomyopathy.

Cardiomyopathy is a group of diseases that impair the heart's ability to pump blood, increasing the risk of heart failure. Although cardiomyopathy affects around 30 million people worldwide, treatment options remain limited. A preclinical study published in Nature Cardiovascular Research found that an ALPK3 gene therapy prevented cardiomyopathy in newborn mice and reversed established disease in adult mice. The therapy also restored the strength and regularity of contractions in human heart organoids carrying disease-causing variants in ALPK3.

'Genetic forms of cardiomyopathy are a major reason why children need heart transplants,' said Dr James McNamara, team leader at Murdoch Children's Research Institute (MCRI) in Melbourne, Australia, and first author of the study. '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.'

Variants in ALPK3 can cause severe cardiomyopathy, with affected children often requiring lifelong medication, repeated surgical procedures and, when the disease progresses, potentially a heart transplant. The researchers designed a gene therapy using an adeno-associated virus (AAV) to deliver a full-length, healthy copy of ALPK3 to heart muscle cells. The AAV was engineered to favour expression of the gene in cardiomyocytes, the cells responsible for the contraction of the heart.

Dr McNamara's team first developed a mouse model of ALPK3 cardiomyopathy that replicated the early onset and severity seen in people with the condition. In newborn mice, a single administration prevented the development of heart dysfunction. When the researchers treated six-week-old mice that already had established cardiomyopathy, the therapy reversed abnormalities in heart structure and restored measures of cardiac function to levels comparable with healthy mice.

The researchers then recreated the disease in human heart organoids made from human pluripotent stem cells. The organoids carried the same ALPK3 variant as the mouse model. Treatment with the gene therapy restored contractile force and reduced abnormal beating in the organoids.

The scientists then investigated whether the gene therapy could be used to target other genetic forms of cardiomyopathy. Using a foundational AI model, they identified several genes whose loss was predicted to have a damaging effect on cardiomyocyte function alongside reduced ALPK3 expression. The strongest predicted interaction was with TTN, which encodes the protein titin. The researchers found that the gene therapy improved contractile function in human cardiac organoids carrying TTN-truncating variants, which result in a shortened protein. These variants account for up to 25 percent of cases of dilated cardiomyopathy.

'Further safety studies are needed before we start human trials, but we have been blown away by the preclinical results,' said Professor Enzo Porrello, director of stem cell medicine at MCRI and senior author of the study. 'We are now seeking commercial partners to take this gene therapy into human clinical trials.'

The broader potential of the gene therapy remains to be explored, including determining which other forms of genetic cardiomyopathy may respond to ALPK3 delivery, and whether the findings can be translated into human clinical trials.