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MicroRNA Leaps Ahead: Alnylam-Isis Venture, Regulus, Shows Its Drug Works in Animals With Heart Failure

Xconomy San Diego — 

The scientific community, and Wall Street, will be buzzing this week about microRNA. That’s because a Carlsbad, CA-based company called Regulus Therapeutics and its collaborators have suggested for the first time that a drug that blocks microRNA can prevent and treat heart failure in animals.

Regulus, a joint venture of Cambridge, MA-based Alnylam Pharmaceuticals (NASDAQ: ALNY) and Carlsbad, CA-based Isis Pharmaceuticals (NASDAQ: ISIS) is breaking the news today online in Nature. The researchers found in a series of experiments that a tiny strand of RNA called mir21 is overactive in heart failure, and contributes to a stress reaction that causes enlargement of the muscle and inefficient blood pumping. When the scientists designed an antisense drug to specifically block mir21, it prevented those changes in the heart muscle of mice, and was able to reverse that condition in mice who already had the disease, researchers said.

MicroRNAs weren’t discovered until 1993 in worms, and not until 2001 in humans. They are thought to have big potential as drugs, because they can affect not just one gene or protein in isolation, but full networks of genes-a strategy which might be useful in treating complex diseases like diabetes or congestive heart failure, where multiple genes can get messed up. Heart failure, which can occur after stress from a heart attack, certain infections, or high blood pressure, affects about five million patients in the U.S.

“This is big news for the field,” says Kleanthis Xanthopoulos, CEO of Regulus. “This is the first time we believe anyone has demonstrated a therapeutic affect of a drug to inhibit microRNA.”

Until this finding, researchers have been only been able to show microRNAs can have an impact on “surrogate” measurements that suggest early promise against a disease but don’t say for sure whether the drug is really altering the disease. Examples are when a treatment lowers cholesterol, it might reduce the risk of heart attack, or when a drug shrinks tumors, it might help cancer patients live longer, Xanthopoulos says.

The research involved collaborators from Regulus, Alnylam, the University of Wuerzburg in Germany, the University of California, San Francisco, King’s College in London, Heidelberg University in Germany, Northwestern University in Evanston, IL, and the Rockefeller University in New York.

“This exciting research defines an entirely new potential strategy for intervention, where antagonism of a single microRNA could result in correction of the disease pathways of heart failure,” said Eugene Braunwald, a professor at Harvard Medical School, in a statement released by Regulus and Alnylam.

The researchers found that when mice were put into heart failure—a chronic condition in which the heart becomes enlarged and fails to efficiently pump blood—they got better in a hurry when they were given a drug to block mir21. They were given three daily injections of the drug close to the heart, and within two to three weeks, their hearts shrunk 30 percent to 40 percent back to normal size, and had their blood pumping ability restored to normal, Xanthopoulos says. “It’s a spectacular finding,” he says.

Before everybody gets too carried away, there always caveats with this type of research. This paper only followed mice for two to three months, so there’s no sense of how long this effect might last. The next step will be to see if the finding can be replicated in pigs, a larger animal with heart tissue that more closely resembles a human. The earliest point this drug could enter human clinical trials would be within a couple years, Xanthopoulos says. Since no microRNA drug has ever been tested in people, it’s probably a safe bet that the FDA will be a little extra careful before allowing the company to go ahead.

Regulus isn’t even saying for sure if mir21 is its lead therapeutic candidate. It’s one of a handful of leading projects at the company, Xanthopoulos says, along with a program against the herpes simplex virus (cold sores). We’ll learn more when Xanthopoulos and Alnylam CEO John Maraganore will take questions like these tomorrow morning on a conference call with investors at 8:30 am Eastern time, before the markets open.


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