Ville de Bou-Ismail

Advanced in the treatment of cardiac fibrosis

A study signed by Dr Samir OUNZAIN and Prof. Thierry Pedrazzini, Associate Professor at FBM and Director of the Experimental Cardiology Unit of the CHUV Heart-Vessel Department, shows that a non-coding RNA molecule can be targeted to curb cardiac fibrosis following myocardial infarction and improve the function of the heart.

From left to right: Samir Ounzain, Isabelle Plaisance, Thierry Pedrazzini et Rudi Micheletti © Laurianne Aeby, SAM-CHUV

The study published on June 21, 2017 in the journal Science Translational Medicine demonstrated for the first time the importance of a non-coding RNA (ribonucleic acid) in the regulation of cardiac fibroblast activity and the development of fibrosis.

Cardiovascular disorders, particularly coronary heart disease, are the leading cause of illness and death in developed countries. The human heart contains about 5 billion muscle cells. It is estimated that during an infarct about one billion of these cells, cardiomyocytes, die. These cardiomyocytes are never replaced. In contrast, a fibrous scar is produced by activated fibroblasts in the damaged heart. Although essential during the acute phase following infarction, cardiac fibrosis is very deleterious in the long term. Indeed, because this zone does not contract, it helps to maintain stress on the heart muscle still alive. In the end, the function is degraded and heart failure occurs. This condition is critical for the patient who is in a potentially fatal situation. Paradoxically, no treatment of heart diseases specifically targets fibroblasts.

"In this study, we are not targeting any of the more than 20,000 genes in the human genome that encode proteins. On the contrary, we were interested in RNA produced by the non-coding genome. This part of the genome, which represents 98% of the genome, produces in particular long non-coding RNAs that play fundamental roles in the regulation of cellular functions. By targeting these non-coding RNAs, we can control the identity and behavior of the cells, "says Thierry Pedrazzini.

The study therefore identified a non-coding RNA molecule that the authors called Wisper. This molecule controls the function of heart fibroblasts, particularly their ability to proliferate and produce cardiac fibrosis. When Wispin vivo is targeted in an animal model of myocardial infarction, fibrosis is greatly diminished, remodeling of the cardiac tissue is attenuated and the function of the heart is improved.

What makes the therapeutic benefit more interesting than the proteins traditionally targeted by the pharmaceutical industry? Beyond our ability to control the biology of fibroblasts, it is found that wispers specifically produced by cardiac fibroblasts. This unique property allows to consider increased efficiency and treatment minimizing side effects. Indeed, if no other cell than the cardiac fibroblasts express Wisper, no other cell will be affected by the treatment. This particularity of the long non-coding RNA allows us to hope for the development of a whole new range of therapeutics, for many pathologies, as demonstrated today for heart diseases.