Brugada syndrome—characterized by an often fatal irregular heartbeat (arrhythmia)—causes sudden cardiac death in relatively young, otherwise healthy individuals between 30 and 40. However, available therapies for the syndrome and other cardiac arrhythmias, which cause 400,000 sudden deaths each year in the United States alone, are limited and even dangerous. Paradoxically, most antiarrhythmic agents do not prevent arrhythmias but instead can provoke arrhythmias.

Scientists rescued mice with mutations in the gene encoding the cardiac sodium channel NaV1.5 identified in Brugada Syndrome patients from disease symptoms using gene therapy. The gene therapy strategy utilizes MOG1, a chaperone protein involved in trafficking of the cardiac sodium channel NaV1.5 to the cell surface, offering an alternative to targeting SCN5A—the gene encoding NaV1.5—which is too large to be subcloned into adeno-associated virus serotype 9 (AAV9) vectors or may not be suitable for gene therapy.

“Overall, our strategy of targeting a small chaperone protein regulating protein trafficking may be used to treat sodium channelopathies with defective protein trafficking,” wrote the authors. “A similar approach could be applied to other diseases for which the disease-causing genes exceed the capacity for delivery by AAV.”

The findings were published in Science Translational Medicine in a paper titled, “Gene therapy targeting protein trafficking regulator MOG1 in mouse models of Brugada syndrome, arrhythmias and mild cardiomyopathy.”

Mutations in SCN5A, encoding cardiac sodium channel NaV1.5, cause 25 to 30% of Brugada syndrome cases. Previously, researchers had found that a small 20-kDa chaperone protein MOG1 binds to NaV1.5 and promotes the trafficking of NaV1.5 to the cell surface but does not affect the sodium channel kinetics or conductance of single sodium channels. MOG1 appears to be a specific regulatory protein of Nav1.5 and cardiac sodium current density and does not affect other cardiac ion channels and ionic currents.

In this study, researchers from the Cleveland Clinic developed a knock-in mouse model of Brugada syndrome using an SCN5A mutation identified in multiple Brugada syndrome families (Scn5aG1746R/+). Qing K. Wang and colleagues then tested AAV9–MOG1 gene therapy in the mouse model, finding that treatment reversed sodium channel/current defects and corrected cardiac electrophysiological abnormalities and clinical features associated with Brugada syndrome. The researchers supported this strategy by applying it to another heterozygous humanized knock-in mouse model expressing a different SCN5A mutation (p.D1275N). In this model, AAV9-MOG1 increased cell surface NaV1.5 expression, enhanced cardiac sodium current density, and rescued the mild dilated cardiomyopathy (DCM) and cardiac arrhythmia.

While this gene therapy strategy with AAV9-MOG1 worked with these SCN5A mutations associated with Brugada syndrome, several hundreds of SCN5A disease-causing variants have been identified. Eighteen SCN5A mutations are considered pathogenic variants for DCM, such as p.D1275N used in this study. However, it remains to be determined whether AAV9-MOG1 gene therapy can be extended to more severe forms of DCM and heart failure.