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

Abstract

Brugada syndrome (BrS) is a fatal arrhythmia that causes an estimated 4% of all sudden death in high-incidence areas. <i>SCN5A</i> encodes cardiac sodium channel Na_V1.5 and causes 25 to 30% of BrS cases. Here, we report generation of a knock-in (KI) mouse model of BrS (<i>Scn5a^G1746R/+</i>). 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 (<i>I</i>_Na) and increased <i>Kcnd3</i> and <i>Cacna1c</i> expression. We developed a gene therapy using adeno-associated virus serotype 9 (AAV9) vector-mediated <i>MOG1</i> delivery for up-regulation of MOG1, a chaperone that binds to Na_V1.5 and traffics it to the cell surface. MOG1 was chosen for gene therapy because the large size of the <i>SCN5A</i> coding sequence (6048 base pairs) exceeds the packaging capacity of AAV vectors. AAV9-<i>MOG1</i> gene therapy increased cell surface expression of Na_V1.5 and ventricular <i>I</i>_Na, reversed up-regulation of <i>Kcnd3</i> and <i>Cacna1c</i> expression, normalized cardiac action potential abnormalities, abolished J waves, and blocked VT in <i>Scn5a^G1746R/+</i> mice. Gene therapy also rescued the phenotypes of cardiac arrhythmias and contractile dysfunction in heterozygous humanized KI mice with <i>SCN5A</i> mutation p.D1275N. Using a small chaperone protein may have broad implications for targeting disease-causing genes exceeding the size capacity of AAV vectors.