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Regulus, Collaborators Publish Data Showing Efficacy of miRNA-Targeting Drug in Animals

Researchers from Regulus Therapeutics and parent firm Alnylam Pharmaceutics, working with investigators from University of Wuerzburg in Germany, published a paper this week showing that an antisense oligonucleotide targeting microRNA-21 could both prevent and treat key features of heart failure in a mouse model of cardiac disease.
As the “first-ever publication of data demonstrating the therapeutic efficacy for a microRNA therapeutic in an animal model of human disease … we believe this is clearly a major de-risking event for the entire microRNA therapeutics field,” Alnylam CEO John Maraganore said this week during a conference call held to discuss the findings.
Based on these and other positive data, Regulus has accelerated its efforts to develop a drug targeting miR-21 as a treatment for cardiovascular and fibrotic diseases and could begin phase I testing of such a compound “within the next couple of years,” Regulus President and CEO Kleanthis Xanthopoulos noted during the call.
He also said that the data, which appeared in the advance online version of Nature, are likely to give a boost to the “very significant interest” that potential partners have shown in Regulus’ miR-21 program. He added that the company expects to provide more information about the status of any potential deal as the program moves “further down the development path.”
Although Regulus isn’t the only company to see the therapeutic potential for microRNA modulation in cardiac disease, “previous studies … have focused on microRNAs that are primarily expressed in cardiomyocytes,” the researchers wrote in Nature. As such, “the role of microRNAs expressed in other cell types of the heart is unclear.”
Building off of the recent discovery that miR-21 is aberrantly expressed in hypertrophic mouse hearts, the investigators examined levels of the miRNA in various cardiac tissues, finding it present in fibroblasts and most highly expressed in cardiac fibroblasts in a mouse model of heart failure. Notably, miR-21 expression was also up to four times greater in the failing human heart versus the non-failing heart.
Additional experimentation revealed that miR-21 over-expression represses the gene Sprouty1, “which in turn results in increased activity of a well-known signaling pathway known as the ERK-MAP kinase pathway,” Regulus CSO Peter Linsley said during the call.
He explained that this effect enhanced interstitial fibroblast survival and increased secretion of fibroblast-derived factors such as fibroblast growth factor, which can lead to the fibrosis and cellular hypertrophy that characterize human heart failure.

As the “first-ever publication of data demonstrating the therapeutic efficacy for a microRNA therapeutic in an animal model of human disease … we believe this is clearly a major de-risking event for the entire microRNA therapeutics field.”

“This model presents a new paradigm in that it assigns a primary role to cardiac fibroblast activation in myocardial disease, rather than regarding fibrosis as secondary to cardiomyocyte damage,” the study authors added in their paper. “Consistent with this hypothesis, left ventricular cardiac tissue samples from patients with end-stage heart failure showed greatly enhanced miR-21 levels, significantly repressed [Sprouty1] protein, and ERK-MAP kinase activation.”
Accordingly, the researchers believe that blocking miR-21 expression in a cardiac disease model should prevent fibrosis. To test this prediction, the team injected chemically modified antisense oligonucleotide specific for miR-21, called antagomir-21, into mice subjected to pressure overload of the left ventricle by transverse aortic constriction or into sham-operated mice,” according to the Nature paper.
In vitro analysis showed that a Cy3-labeled anti-miR-21 molecule was taken up both in cardiac fibroblasts and cardiomyocytes, while intravenously injecting the agent into the jugular vein of mice resulted in strong Cy3 staining throughout the left ventricular myocardium, the researchers wrote. Meanwhile, mice subjected to TAC and treated with antagomir-21 for three consecutive days displayed repressed cardiac miR-21 expression that lasted for up to three weeks.
More importantly, antagomir-21 treatment “restores Spouty1 levels back to normal, and this effect results in normalization of ERK-MAP kinase activity,” Linsley said.
Moreover, “interstitial fibrosis, cardiomyocyte size, and heart weight were significantly increased three weeks after TAC in mice treated with the control, but this effect was strongly attenuated by antagomir-21 treatment,” according to the Nature paper. Treatment of sham-operated mice with antagomir-21 had no notable effect on heart weight or myocardial structure, the researchers noted.
Echocardiography further revealed that the antagomir-21 treatment prevented left-ventricular dilatation and normalized fractional shortening.
“Altogether, these were very encouraging data as they suggested an anti-miR-21 was not only correcting fibrosis, but also significantly correcting those structural and functional [changes associated with] pathologic cardiac remodeling in this animal model,” Linsley said.
But while this kind of “prophylaxis paradigm is interesting, [it is] not necessarily important in the context of treating established heart failure,” he added. “So … we turned to a treatment paradigm where anti-miR-21 or control was administered three weeks after the TAC procedure.”
“Whereas animals treated with control displayed progressive impairment of left ventricular function, as well as interstitial fibrosis and cardiac hypertrophy, animals treated with antagomir-21 showed significant attenuation of the impairment of cardiac function, as well as regression of cardiac hypertrophy and fibrosis,” the researchers wrote. “Thus, our study demonstrates therapeutic efficacy for silencing of miR-21 by antagomirs in a cardiac disease setting.”
Also contributing to the Nature paper were investigators from the University of California, San Francisco, King’s College London, Heidelberg University, Northwestern University, and Rockefeller University.

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