New gene identified for treating malignant cardiac arrhythmias

Cardiac arrhythmias, responsible for a significant proportion of deaths, occur when the heart’s electrical impulses, essential for a steady beat, are disrupted. “Arrhythmias often occur due to slowing of conduction of the electrical impulse through the heart,” explained Gerard Boink, cardiologist at Amsterdam UMC and coordinating author of the study. “Rapid impulse conduction is needed for the heart to beat in a steady rhythm. When this is disturbed, the patient may experience a life-threatening cardiac arrhythmia.”

Overcoming size limitations: a crucial discovery

The challenge in developing gene therapy for cardiac arrhythmias has historically been the size of effective genes. Existing potential genes were simply too large to be delivered effectively into heart muscle cells using viral vectors. “Think of this vector like being a suitcase, up until now most of the relevant genes were just too big to fit in,” Boink stated.

The discovery of S10s, a significantly smaller gene, addresses this crucial obstacle. This gene, identified by researchers in the Department of Medical Biology at Amsterdam UMC, is small enough to fit within an adeno-associated virus (AAV) vector, the most efficient gene delivery platform for the heart. AAV is a small virus that doesn’t cause disease in humans and is often used to carry therapeutic genes into specific cells to treat genetic disorders. It’s considered a safe and effective delivery vehicle due to its ability to target a variety of tissues and its low risk of immune response.

“Finding a small enough gene was of course a crucial first step and in S10s we also have found a gene that may be able to reverse the conduction slowing and allow the heart to beat at its regular rhythm,” said Phil Barnett, senior researcher in the Department of Medical Biology.

From lab to clinical trials

The research team has demonstrated, through studies in animal models, human stem cell-derived heart muscle cells, and computational modelling, that S10s can be successfully introduced into the heart via an AAV vector. This introduction led to faster electrical conduction, suggesting a potential therapeutic solution for preventing cardiac arrhythmias.

“These are great early steps but now we need to continue our research in order to find out if this approach will really translate into clinical practice,” Boink emphasised. “If it does, then we should be able to significantly reduce the occurrence of arrythmias and make a meaningful impact on patient mortality.”

To accelerate the transition from laboratory to clinic, Boink, along with fellow Amsterdam UMC cardiologists Hanno Tan and anaesthesiologist Otto Kirzner, has launched a spin-off company, Pacing Cure. This company aims to serve as a stepping stone to expedite clinical progress.

Follow-up studies, financed by the European Innovation Council and the Dutch Heart Foundation, are already underway in collaboration with various departments at Amsterdam UMC. These studies will continue to explore the potential of S10s gene therapy and pave the way for future clinical trials, bringing hope to millions suffering from life-threatening cardiac arrhythmias.

This study was published in the European Heart Journal.