Therapeutic Inhibition of miR-208a Improves Cardiac Function and Survival During Heart Failure

Rusty L. Montgomery¹, Thomas G. Hullinger¹, Hillary M. Semus¹, Brent A. Dickinson¹,  Anita G. Seto¹, Joshua M. Lynch¹, Christianna Stack¹, Paul A. Latimer¹, Eric N. Olson², Eva van Rooij¹

¹miRagen Therapeutics Inc., 6200 Lookout Road, Boulder, CO 80301, USA and ²Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Background—Diastolic dysfunction in response to hypertrophy is a major clinical syndrome with few therapeutic options.

MicroRNAs act as negative regulators of gene expression by inhibiting translation or promoting degradation of target

mRNAs. Previously, we reported that genetic deletion of the cardiac-specific miR-208a prevents pathological cardiac

remodeling and upregulation of Myh7 in response to pressure overload. Whether this miRNA might contribute to

diastolic dysfunction or other forms of heart disease is currently unknown.

Methods and Results—Here, we show that systemic delivery of an antisense oligonucleotide induces potent and sustained

silencing of miR-208a in the heart. Therapeutic inhibition of miR-208a by subcutaneous delivery of antimiR-208a

during hypertension-induced heart failure in Dahl hypertensive rats dose-dependently prevents pathological myosin

switching and cardiac remodeling while improving cardiac function, overall health, and survival. Transcriptional

profiling indicates that antimiR-208a evokes prominent effects on cardiac gene expression; plasma analysis indicates

significant changes in circulating levels of miRNAs on antimiR-208a treatment.

Conclusions—These studies indicate the potential of oligonucleotide-based therapies for modulating cardiac miRNAs and

validate miR-208 as a potent therapeutic target for the modulation of cardiac function and remodeling during heart

disease progression.

http://circ.ahajournals.org/content/early/2011/09/06/CIRCULATIONAHA.111.030932.abstract