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Miragen, UT Southwestern Show miR-208 Inhibition Improves Survival in Rodent Heart-Failure Models

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By Doug Macron

Researchers from Miragen Therapeutics and the University of Texas Southwestern Medial Center this week published data showing that an inhibitor of microRNA-208 could improve cardiac function and survival rates in mice during heart failure.

“Not only do these findings provide additional validation of miR-208 as a promising target for therapeutic intervention, but they also enhance our understanding of microRNA biology,” Miragen President and CEO Bill Marshall said in a statement.

In the paper, which appeared in Circulation Research, the investigators noted that “chronic and acute stress to the heart results in a pathological remodeling response accompanied by cardiomyocyte hypertrophy, fibrosis, pump failure, myocyte degeneration, and apoptosis, which often culminate in heart failure and sudden death.

“A hallmark of pathological hypertrophy and heart failure is the reactivation of a set of fetal cardiac genes,
including those encoding atrial natriuretic factor, B-type natriuretic peptide, and fetal isoforms of contractile proteins such as skeletal alpha-actin and beta-myosin heavy chain,” they added.

Previously, the UT Southwestern team reported that miR-208, a heart-specific miRNA encoded by an intron of the alpha-MHC gene, is associated with cardiomyocyte hypertrophy, fibrosis, and the expression of beta-MHC in response to stress and hypothyroidism.

Following up on these and other findings, the researchers evaluated locked nucleic acid oligos against miR-208 in rats with hypertension-induced heart failure and found that the treated animals experienced “potent and sustained silencing” of the miRNA target, according to the paper.

Therapeutic inhibition of miR-208 by subcutaneous delivery of the LNAs during heart failure, meantime, dose-dependently prevented “pathological myosin switching and cardiac remodeling while improving cardiac function, overall health, and survival,” they wrote.

“Transcriptional profiling indicates that antimiR-208a evokes prominent effects on cardiac gene expression … [and] plasma analysis indicates significant changes in circulating levels of miRNAs on ... treatment,” they added.

Miragen is currently developing an miR-208 antagonist as a treatment for chronic heart failure and has licensed the right to use Santaris Pharma's LNA technology as therapeutic miRNA inhibitors in cardiovascular disease (GSN 5/26/2011 & 6/24/2010).

The new data provide “strong evidence” that subcutaneous delivery of the LNA-based miRNA antagonists is sufficient to deliver the oligos to the heart in vivo, the researchers concluded.

Additionally, they show that miR-208 inhibition can prevent cardiac remodeling, blunt functional deterioration, and delay lethality during heart disease. However, they cautioned that “it remains unclear whether these effects arise solely from effects on cardiomyocytes as a result of miR-208 ... inhibition or whether there are extracardiac effects” in response to treatment.

“Ongoing experiments will indicate whether this therapeutic benefit can be established in multiple models of heart failure,” they wrote. At the same time, “extensive analyses are required to determine the long-term safety of such agents in various settings,” including in the clinic.


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