Antisense microRNAs will help in the treatment of heart failure
Blocking microRNA restores heart function
NanoNewsNet by materials:
Sanford-Burnham Medical Research Institute – Blocking key heart-failure culprit restores functionIcahn School of Medicine at Mount Sinai – Key Heart Failure Culprit Discovered
U-T San Diego – MicroRNA therapy may help heart failure
American scientists have deciphered how a small fragment of RNA – microRNA-25 – contributes to the progression of heart failure, and have shown that by blocking microRNA-25 antisense RNA, this process can be slowed down.
A study conducted by a group of scientists from the Sanford-Burnham Medical Research Institute, Icahn School of Medicine at Mount Sinai Medical Center (Icahn School of Medicine at Mount Sinai) and the University of California at San Diego (University of California, San Diego), published in the journal Nature, suggests that microRNA-25 may become a new therapeutic target for restoring heart function (Wahlquist et al., Inhibition of miR-25 improves cardiac contractility in the failing heart).
"Even before this study, we knew about the suppression of the SERCA2a gene in heart failure, but we did not know the mechanism," says study leader Mark Mercola, PhD, professor of the Development, Aging and Regeneration Program at Sanford–Burnham, professor of bioengineering at the Jacobs School of Engineering at UC San Diego. "SERCA2a regulates the intake of calcium into the cells of the heart muscle and is important for the contractile function of the heart."
In another study, this gene has already been identified as a target for gene therapy of heart failure.
Knowing that the heart's ability to contract is regulated by calcium intake and that in heart failure, the activity of the SERCA2a calcium pump decreases, Dr. Mercola and his colleagues suggested that in this disease, the level of microRNAs suppressing the function of SERCA2a may be increased.
"Our study shows that a certain microRNA called microRNA-25 is activated in patients with heart failure. And we show that the introduction of an agent blocking microRNA-25 improves function and increases survival to "normal" levels in a mouse model of heart failure," say study participants graduate student Christine Wahlquist (Christine Wahlquist) and postdoctoral student Agustin Rojas Muñoz (Agustin Rojas Muñoz), PhD, from the laboratory of Dr. Mercola in Sanford- Burnham.
Using a high-performance screening system, Valquist and Rojas Munoz screened 875 microRNAs and found one, microRNA-25 (miR-25), which powerfully suppressed calcium uptake by heart cells and was actively expressed in both mouse and human bodies.
Colleagues of Dr. Mercola from the Cardiovascular Research Center (Cardiovascular Research Center) Icahn School of Medicine found that the introduction of a small fragment of RNA, suppressing the effects of microRNA-25, dramatically inhibits the progression of heart failure in mice.
The newly discovered culprit of heart failure – microRNA-25 – is widely represented in heart cells.
Targeting this molecule allowed scientists to successfully slow down the progression
heart failure in mice with a model of this disease.
(Photo: icahn.mssm.edu )
"In this study, we not only identified one of the key cellular processes leading to heart failure, but also demonstrated the therapeutic potential of blocking this process," says co–lead author of the study Dongtak Jeong, PhD, postdoctoral fellow in the laboratory of Roger Hajjar, MD, co-director of the study, director of the Scientific andResearch Center for Cardiovascular Diseases and Professor of Medicine at the Icahn School of Medicine.
"Before the advent of high–performance functional screening, our chance to decipher complex biological processes associated with diseases such as heart failure was close to the chance to find a needle in a haystack," Dr. Mercola continues. "Our laboratory is a pioneer in the use of high-throughput robotic methods in the search for new targets in heart failure. Now, to find the microRNAs that interfere with the normal function of the heart muscle, we can "sift" the entire genome."
Heart failure is the main cause of hospitalization in old age. Currently used medications only temporarily alleviate the symptoms of this disease. They do not improve heart function and do not stop the progression of the disease.
"This discovery represents a promising path to the development of drugs that work in the muscle cells of a diseased heart and treat the disease itself, and not just its symptoms," concludes Dr. Mercola.
The activity of the SERCA2a gene in this study was increased using a technology that allows the inactivation of microRNA-25 antisense RNA. An antisense RNA molecule is a sequence complementary to a specific RNA molecule, called in this case "semantic", which it inactivates. By binding to RNA target molecules, antisense molecules prevent them from performing the function of a template for protein synthesis.
"The concept is compelling, and I think the idea is very interesting," says Neil Gibson, chief scientist at Regulus Therapeutics, a biotech company developing microRNA–based drugs. "I think microRNAs in the treatment of cardiovascular diseases are promising and can play an interesting role."
However, on the way of translating the results of this study into a safe and effective drug, scientists will face more than one problem, Gibson believes. One of them is the delivery of antisense RNA to the cells of the heart muscle, where its targets are located. With systemic administration of antisense drugs, they accumulate well in the liver, kidneys, fat cells, macrophages and much worse in the heart. The second problem is the strict regulations of the FDA.
"These are all challenges that will have to be faced, but this only underscores the need to improve delivery technology to specific cell types or specific organs," Gibson comments.
Currently, Professor Hajjar's laboratory is developing new gene therapy drugs for the treatment of heart failure. One of the drugs currently undergoing phase IIb/III clinical trials uses a modified viral vector to deliver a gene encoding SERCA2a. Another drug undergoing preclinical development uses an inactivated virus to deliver a gene called SUMO-1 encoding a protein necessary for modification of SERCA2a.
Portal "Eternal youth" http://vechnayamolodost.ru20.03.2014