A team including Sanford-Burnham Medical Research scientists has identified a form of RNA that plays a key role in inducing heart failure.
Called miR-25, the molecule is a short fragment of RNA, called microRNA. In a model of heart failure in mice, increasing the level of miR-25 reduced the efficiency of heart muscle contraction. Inhibiting miR-25 halted heart failure that had already been established.
The study was published Wednesday in the journal Nature. Scientists from the Icahn School of Medicine at Mount Sinai in New York City and UC San Diego collaborated with Sanford-Burnham scientists in the study.
The microRNA molecule blocks activity of a gene called SERCA2a, which regulates the flow of calcium ions into cardiac tissue. The gene has been identified in another study as a target for gene therapy in heart failure.
In this study, co-led by Sanford-Burnham heart disease researcher Mark Mercola, the gene activity was boosted by using technology called antisense to inactivate miR-25. Antisense RNA molecules form a complementary sequence to the specific RNA molecule, called the "sense" molecule, they inactivate. The antisense molecules bind to the targeted RNA molecules, which prevents them from serving as a template for protein production.
"The concept is compelling and I think the idea is very interesting," said Neil Gibson, chief scientific officer of Regulus Therapeutics, a San Diego biotech developing microRNA drugs. "I think there's a number of opportunities in cardiovascular disease where microRNAs may play an interesting role."
Some challenges lie ahead in converting the research into a safe and effective drug, Gibson said. One is how to get the antisense microRNA inside the heart muscle cells, where the target microRNAs are found. Meeting the regulations of the U.S. Food and Drug Administration is another.
"Trying to develop something in cardiovascular disease is going to be subject to all the stringent FDA requirements that they would impose on that type of therapeutic approach," Gibson said.
When antisense drugs are given systemically, they accumulate well in the liver, kidneys, adipose cells and a kind of white blood cell called macrophages, Gibson, said, but not so much in the heart.
"These are all challenges that can be addressed, but it just highlights that we really need to improve this technology in a way to preferentially deliver to specific cell types or specific organs," Gibson said.
Antisense drugs have been under development for decades, most notably by Carlsbad's Isis Pharmaceuticals. In January of last year, an Isis drug that lowers cholesterol and triglyceride levels was approved by the FDA. The drug, called Kynamro, works in the liver. It's being sold by Isis partner Genzyme. Regulus was founded by Isis and another antisense biotech, Alnylam Pharmaceuticals, of Cambridge, Mass.
In the heart failure study, the culprit molecule was identified with a functional screening system developed at Sanford-Burnham Mercola said in a Sanford-Burnham press release. Mercola is a professor in the Development, Aging, and Regeneration Program at Sanford-Burnham and a professor of bioengineering at UC San Diego Jacobs School of Engineering.
"Before the availability of high-throughput functional screening, our chance of teasing apart complex biological processes involved in disease progression like heart failure was like finding a needle in a haystack," Mercola said in the release. "The results of this study validate our approach to identifying microRNAs as potential therapeutic targets with significant clinical value."
The screen searched through all human microRNAs to find those linked to heart failure. Colleagues at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai found that injecting the antisense complement to miR-25 stopped heart-failure progression in mice, improved cardiac function and survival.
Heart failure is a progressive loss of the heart's ability to pump blood. It can be caused by heart attacks, high blood pressure, diabetes and other conditions. As heart failure worsens, patients become increasingly restricted in their physical activities. The disease affects nearly six million Americans.
"In this study, we have not only identified one of the key cellular processes leading to heart failure, but have also demonstrated the therapeutic potential of blocking this process," said co-lead study author Dongtak Jeong in the press release. Jeong is, a post-doctoral fellow at Icahn School of Medicine at Mount Sinai in the laboratory of the study's co-senior author Roger J. Hajjar.
The study provides "key evidence" to allow developing miR-25 as a new drug target, Hajjar said. His lab is studying gene therapy, using a virus to deliver the SERCA2a gene. That gene makes an enzyme found in healthy heart muscle cells.
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