Gene therapy targeting protein trafficking regulator MOG1 in mouse models of Brugada syndrome, arrhythmias, and mild cardiomyopathy.

Brugada syndrome (BrS) is a fatal arrhythmia that causes an estimated 4% of all sudden death in high-incidence areas. encodes cardiac sodium channel Na1.5 and causes 25 to 30% of BrS cases. Here, we report generation of a knock-in (KI) mouse model of BrS (). Heterozygous KI mice recapitulated some of the clinical features of BrS, including an ST segment abnormality (a prominent J wave) on electrocardiograms and development of spontaneous ventricular tachyarrhythmias (VTs), seizures, and sudden death. VTs were caused by shortened cardiac action potential duration and late phase 3 early afterdepolarizations associated with reduced sodium current density () and increased and expression. We developed a gene therapy using adeno-associated virus serotype 9 (AAV9) vector-mediated delivery for up-regulation of MOG1, a chaperone that binds to Na1.5 and traffics it to the cell surface. MOG1 was chosen for gene therapy because the large size of the coding sequence (6048 base pairs) exceeds the packaging capacity of AAV vectors. AAV9- gene therapy increased cell surface expression of Na1.5 and ventricular , reversed up-regulation of and expression, normalized cardiac action potential abnormalities, abolished J waves, and blocked VT in mice. Gene therapy also rescued the phenotypes of cardiac arrhythmias and contractile dysfunction in heterozygous humanized KI mice with mutation p.D1275N. Using a small chaperone protein may have broad implications for targeting disease-causing genes exceeding the size capacity of AAV vectors.