A DRUG seems to protect mice from heart failure even when enormous pressure is placed on their hearts. If the results can be replicated in humans, it could help millions of people avoid some of the long-term consequences of a heart attack.
Heart failure is a chronic condition in which the heart is unable to pump enough blood to meet the body’s needs, leaving people tired, breathless and at high risk of subsequent heart attacks. It affects more than 20 million people worldwide and often occurs as a result of a heart attack or long-term stress on the heart from high blood pressure.
The new drug targets a micro RNA – a molecule that inhibits the expression of a network of genes. Researchers recently discovered that a micro RNA called miR-208 is implicated in heart failure and that mice engineered to lack the gene for miR-208 are protected against heart failure (Science, ).
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So William Marshall at in Boulder, Colorado, and his colleagues developed an injectable “antagomir” – a string of nucleic acids designed to bind to miR-208 and block its action.
They injected the antagomir into the hearts of healthy mice then severely stressed them by tying a band around the major blood vessel that carries blood away from the heart. Blocking the inhibitory effects of miR-208 caused an increase in gene expression and the hearts did not develop the usual signs of heart failure, which include enlarged muscle cells and a switch towards a fetal form of heart protein that makes the heart beat less efficiently (see diagram).
“This is the first time that a drug has been able to reverse the switch [to the fetal protein] and take it back to the [adult] form,” says Marshall, who presented the results at a meeting in Cambridge, UK, last week.
He is now trying to replicate the results in sheep and hopes that the drug could eventually be injected into human hearts, perhaps alongside surgery after a heart attack in order to protect people against heart failure.
“If the data are reproducible in humans, there will be vast clinical potential for applying miR-208 antagonists in the treatment of a number of cardiac diseases,” says Hasse Brønnum, a researcher in molecular cardiology at the University of Southern Denmark in Odense – although he cautions that Marshall has not yet shown that the antagomir is protective after heart attacks.
Sakari Kauppinen of in Hørsholm, Denmark, agrees. “miR-208 is a very exciting target for the treatment of heart disease,” he says. “What’s remarkable is that the effect of antagonising micro RNAs is so long-lasting.” In the case of the miR-208 antagomir, a single injection appears to inhibit the micro RNA for up to 90 days.
Santaris is currently conducting the first human trial of an antagomir against a different micro RNA, which is implicated in hepatitis C.
The development of antagomirs “represents a paradigm shift in the development of novel drugs”, Kauppinen says, not just in heart disease but also in some cancers that are linked to micro RNAs.
