MicroRNA Blocker Prevented Heart Failure In Mice

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Main Category: Cardiovascular / Cardiology
Also Included In: Genetics;  Biology / Biochemistry
Article Date: 01 Dec 2008 - 2:00 PDT

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An international team of scientists from universities and private industry has discovered that a tiny scrap of genetic material called microRNA-21 (miR-21) regulates gene signalling pathways that are active in heart failure and a new experimental drug was able to silence these pathways and prevent heart failure in mice.

The study was led by Dr Thomas Thum and a team of scientists based at the University of Wuerzburg in Germany, and the experimental drug was supplied by Regulus Therapeutics, a joint venture between Alnylam Pharmaceuticals Inc and Isis Pharmaceuticals Inc of the US, that was formed to discover and make commercial use of microRNA-based therapeutics. The findings were published in an advance online publication in Nature on 30 November.

Thum and colleagues found that miR-21 was over-expressed in the failing human heart and affected the structure and working of heart muscle through regulation of a gene signalling pathway involved in responding to stress.

They also targeted miR-21 and prevented heart failure in laboratory mice by using a new experimental drug called antisense oligonucleotide (an anti- miR-21 that is also called an "antagomir"). Furthermore, they showed that giving mice anti-miR-21 after established heart failure appeared to reverse some of the damage caused by the condition.

President and Chief Executive Officer of Regulus Therapeutics, Dr Kleanthis G Xanthopoulos, said:

"We believe that this is the first study to clearly demonstrate therapeutic efficacy for targeting microRNAs in an animal model of human disease."

Dr Peter Linsley, Chief Scientific Officer of Regulus Therapeutics explained that perhaps the most important aspect from a therapeutic point of view was that the study showed it might be possible to target entire disease pathways with one drug:

"This study has revealed a key role for miR-21 in regulating a major stress-response pathway in the failing heart. Administration of anti-miR-21 led to a striking effect in preventing and treating cellular, morphologic, and functional features of heart failure in a well-established animal model," he added.

Heart failure, also called congestive heart failure (CHF), is where the heart can't supply enough blood to the rest of the body and occurs when the heart is under sudden enormous or chronic stress. It can follow a heart attack, some types of infection, or be caused by high blood pressure or genetic factors. There are some 5 million heart failure patients in the US, where it kills about 600,000 people a year.

MicroRNAs are small scraps of RNA comprising around 20 nucleotides (the smallest element of genetic code, like letters of the genetic alphabet) and it is only recently that scientists have discovered their power which is they can regulate the expression (switching on and off) of a large number of human genes (they are like "master controllers").

When microRNAs don't appear in the right place at the right time within cells, studies have shown this is linked to various diseases including cancer, viral infections, inflammatory diseases and metabolic disorders. The potential to use them as targets for drugs is obvious and possibly explains why this is one of the fastest growing areas of development for new drugs and treatments.

Scientists already knew that microRNA was involved in switching genes on and off in the heart, but the underlying mechanisms and how they relate to the development of particular types of heart disease and their potential as drug targets were still relatively unknown.

Thum and colleagues discovered that miR-21 was expressed in the heart's fibroblast cells (cells that make the scaffolding of collagen or connective tissue that hold the shape of the organ) and were in greater numbers in lab mice bred to have heart failure and also in human tissue from patients who had had heart failure.

In this study they showed that increasing expression of miR-21 changed the way that signals behaved in a previously unknown stress response pathway that involved the gene sprouty-1 and the MAP-kinase signaling pathway. In turn, increasing the activity of the MAP-kinase pathway led to a number of signs of heart failure, such as enhanced fibroblast survival, increased secretion of factors like fibroblast growth factor, tissue scarring (fibrosis), and cardiac dysfunction including cellular hypertrophy (getting too big).

The researchers proved they could administer anti-miR-21 effectively to the heart by monitoring it with fluorescence staining. Then, in a mouse transaortic constriction model of human heart failure, they showed that anti-miR-21 silenced increased expression of miR-21 and corrected downstream changes in sprouty-1 and MAP-kinase signaling.

They went on to show that anti-miR-21 stopped tissue scarring and reversed the hypertrophy of cardiomyocytes that results in increased weight of the heart that is characteristic of heart failure in lab mice and humans.

And finally, they demonstrated that anti-miR-21 corrected heart failure defects including left ventricular dilatation and fractional shortening.

Anti-miR-21 showed the most statistically significant improvement in the heart failure mouse model when given before induction of heart failure and for as long as three weeks afterwards, the authors reported in a separate press statement.

"MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts."
Thomas Thum, Carina Gross, Jan Fiedler, Thomas Fischer, Stephan Kissler, Markus Bussen, Paolo Galuppo, Steffen Just, Wolfgang Rottbauer, Stefan Frantz, Mirco Castoldi, Jürgen Soutschek, Victor Koteliansky, Andreas Rosenwald, M. Albert Basson, Jonathan D. Licht, John T. R. Pena, Sara H. Rouhanifard, Martina U. Muckenthaler, Thomas Tuschl, Gail R. Martin, Johann Bauersachs & Stefan Engelhardt.
Nature, advance online publication 30 November 2008.
doi:10.1038/nature07511

Click here for Abstract.

Sources: Journal Abstract, Regulus Therapeutics.

Written by: Catharine Paddock, PhD
Copyright: Medical News Today
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