ABSTRACT
Facioscapulohumeral muscular dystrophy (FSHD), one of the most common muscular dystrophies, is caused by an abnormal expression of the DUX4 gene in skeletal muscles, resulting in muscle weakness. In this study, we investigated MT-DUX4-ASO, a novel gapmer antisense oligonucleotide (ASO). MT-DUX4-ASO decreased the expression of DUX4 and its target genes in FSHD patient-derived myoblasts. For the first time, we demonstrated that a systemically administered ASO, even without a ligand for drug delivery, could significantly improve muscle injury and motor function in the ACTA1-MCM/FLExDUX4 (DUX4-TG) mouse model of FSHD. Tamoxifen (TMX) injection transiently induces skeletal-muscle-specific DUX4 expression in DUX4-TG mice, while the skeletal muscles of TMX-untreated DUX4-TG mice have leaky DUX4 expression in a small subset of myofibers similar to those of FSHD patients. Subcutaneous 10 mg/kg of MT-DUX4-ASO at two-week intervals significantly suppressed muscular DUX4 target gene expression, histological muscle injury, and blood muscle injury marker elevation in TMX-untreated DUX4-TG mice. Notably, MT-DUX4-ASO at 10 mg/kg every other week significantly prevented the TMX-induced declines in treadmill test running speed and muscle force in DUX4-TG mice. Thus, the systemically administered unconjugated MT-DUX4-ASO suppressed disease progression in DUX4-TG mice, extending the potential of unconjugated ASOs as a promising FSHD treatment strategy.
ABSTRACT
BACKGROUND: The endothelin (ET) system is activated in failing hearts. Congestive heart failure frequently is associated with ventricular arrhythmias, which may result from electrical remodeling such as changes of ionic current density and heterogeneous action potential prolongation. We examined the effects of long-term ET(A) receptor blockade on the electrophysiological properties of ventricular cells, the surface ECG, and the survival in BIO 14.6 cardiomyopathic hamsters. METHODS AND RESULTS: Membrane currents and action potentials were recorded from left ventricular cells isolated from normal F1beta hamsters and cardiomyopathic BIO 14.6 hamsters untreated and chronically treated with TA-0201, an ET(A) receptor antagonist. In ventricular cells of untreated BIO 14.6 hamsters, the action potential duration was prolonged and the densities of the L-type Ca2+ current (I(Ca,L)), the transient outward current (I(to)), the delayed rectifier K+ current (I(K)), and the inward rectifier K+ current (I(K1)) were decreased compared with those of F1beta hamsters. Long-term treatment with the ET(A) receptor antagonist significantly attenuated action potential duration prolongation and reduction of I(to), I(K), and I(Ca,L) in BIO 14.6 ventricular cells. Long-term ET(A) receptor blockade prevented the QT prolongation and ventricular arrhythmias and improved the survival rate in the cardiomyopathic hamsters. CONCLUSIONS: Long-term treatment with an ET(A) antagonist inhibits electrical remodeling such as downregulation of K+ and Ca2+ currents, action potential prolongation, and the increased QT interval and thereby suppresses ventricular arrhythmias in cardiomyopathic hearts. ET(A) receptor blockade may provide a new strategy for the prevention of ventricular arrhythmias associated with heart failure.
