A discovery by researchers at Amsterdam UMC and Johns Hopkins University could lead to a new gene therapy for treating malignant cardiac arrhythmia, a condition responsible for a significant number of deaths worldwide. The gene, named SCN10a-short (S10s), was identified in the search for a one-off gene therapy that could improve heart function and prevent cardiac arrhythmias. Results of the research are published in the European Heart Journal.
“Arrhythmias often occur due to slowing of conduction of the electrical impulse through the heart. 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,” said Gerard Boink, MD, PhD, a cardiologist at Amsterdam UMC and the coordinating author of the study. “Among others, conduction slowing and arrhythmias can occur in patients who suffer from a heart attack, heart failure, or from a genetic cause.”
The discovery of S10s could overcome the hurdle of delivering a gene therapy for these cardiac conditions. Until now, genes identified that could potentially fix conduction issues have been too large to deliver into heart muscles using an AAV vector. S10s, however, are small enough to fit into the delivery vector, making it a strong candidate for the development of a gene therapy.
“The search for a gene therapy is not a new one but until now we had the pretty fundamental problem that the potentially effective genes we had identified were too large to be transported via a viral vector into heart muscle cells,” said Boink.
S10s addresses the need to overcome reduced sodium current (INa) in heart cells, which is implicated in various arrhythmia conditions such as Brugada Syndrome and arrhythmias related to heart attacks or heart failure. According to the research team’s findings, increasing the sodium current via S10s therapy may offer a therapeutic solution for patients suffering from these conditions. The team has demonstrated that introducing S10s into animal models and human heart muscle cells derived from stem cells increased the speed of electrical impulses, a critical factor for maintaining steady heart rhythms.
“Our present work evaluated the potential of S10s overexpression as a gene therapy for cardiac arrhythmias that stem from reduction in INa,” the researchers wrote. “Our data from ex vivo, in vivo, in vitro, and in silico experiments provide support for the concept that introduction of S10s in ventricular cardiomyocytes increases INa, thereby improving cardiac conduction and importantly compensating for INa insufficiency and mitigating the associated risk for arrhythmias.”
Current treatment options for malignant cardiac arrhythmia include medications and invasive surgical procedures. Medications can require lifelong management, while surgeries may involve complex, invasive procedures that have varying levels of success.
The investigators noted that while the gene therapy was successful in preclinical models, it is still early in the development process. They acknowledged that additional testing in large animal models and further investigation into the mechanism of action of S10s will be crucial to ensure its safety and efficacy for human patients.
To aid in this process, Boink and colleagues have launched a spin-off company, Pacing Cure. The company will conduct further testing in animal models to prepare the therapy for human trials. “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 said.
Further testing will include using intramyocardial injections to deliver S10s directly into the heart, where it can have the greatest effect on abnormal conduction areas. This targeted approach is expected to minimize side effects while delivering an effective dose of the gene.
