Gene therapy targeting protein trafficking regulator MOG1 in mouse models of Brugada syndrome, arrhythmias, and mild cardiomyopathy.
Gang YuSusmita ChakrabartiMiroslava TischenkoAi-Lan ChenZhijie WangHyosuk ChoBrent A FrenchSathyamangla Venkata Naga PrasadQiuyun ChenQing Kenneth WangPublished in: Science translational medicine (2022)
Brugada syndrome (BrS) is a fatal arrhythmia that causes an estimated 4% of all sudden death in high-incidence areas. SCN5A encodes cardiac sodium channel Na V 1.5 and causes 25 to 30% of BrS cases. Here, we report generation of a knock-in (KI) mouse model of BrS ( Scn5a G1746R/+ ). 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 Na ) and increased Kcnd3 and Cacna1c expression. We developed a gene therapy using adeno-associated virus serotype 9 (AAV9) vector-mediated MOG1 delivery for up-regulation of MOG1, a chaperone that binds to Na V 1.5 and traffics it to the cell surface. MOG1 was chosen for gene therapy because the large size of the SCN5A coding sequence (6048 base pairs) exceeds the packaging capacity of AAV vectors. AAV9- MOG1 gene therapy increased cell surface expression of Na V 1.5 and ventricular I Na , reversed up-regulation of Kcnd3 and Cacna1c expression, normalized cardiac action potential abnormalities, abolished J waves, and blocked VT in Scn5a G1746R/+ mice. Gene therapy also rescued the phenotypes of cardiac arrhythmias and contractile dysfunction in heterozygous humanized KI mice with SCN5A mutation p.D1275N. Using a small chaperone protein may have broad implications for targeting disease-causing genes exceeding the size capacity of AAV vectors.
Keyphrases
- gene therapy
- cell surface
- left ventricular
- mouse model
- poor prognosis
- binding protein
- heart failure
- high fat diet induced
- neoadjuvant chemotherapy
- early onset
- amino acid
- heat shock protein
- squamous cell carcinoma
- oxidative stress
- long non coding rna
- skeletal muscle
- cancer therapy
- risk factors
- protein protein
- human health
- metabolic syndrome
- catheter ablation
- transcription factor
- case report
- risk assessment
- genome wide
- lymph node
- dengue virus
- small molecule
- atrial fibrillation
- heat stress