Straight from the heart

NEW YORK & SAN DIEGO—There is good news for the nearly six million Americans who suffer from heart failure, a condition that arises when the heart becomes weak and cannot pump enough blood and oxygen throughout the body. With 800,000 new cases per year in the United States alone and the likelihood that the prevalence of heart failure will rise in the next 20 to 25 years, it has “opened up a new avenue for a problem with unmet needs,” according to Dr. Roger J. Hajjar, director and Arthur & Janet C. Ross Professor of Medicine of the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai.

A team of cardiovascular researchers has identified a small but powerful new player in the onset and progression of heart failure and successfully blocked the newly discovered culprit to halt the debilitating and chronic life-threatening condition in its tracks. The findings of these researchers from Hajjar’s laboratory and the Sanford-Burnham Medical Research Institute and the University of California, San Diego, were published in the journal Nature on March 12.

The investigators identified a tiny piece of RNA called miR-25 that blocks a gene known as SERCA2a, which regulates the flow of calcium within heart muscle cells. Decreased SERCA2a activity is one of the main causes of poor contraction of the heart and enlargement of heart muscle cells leading to heart failure. Using a functional screening system developed by researchers at Sanford-Burnham, the research team discovered that miR-25 acts pathologically in patients suffering from heart failure, delaying proper calcium uptake in heart muscle cells.

“In a multidisciplinary approach to modern medicine, we used high-throughput screening to understand the physiology of the heart, come up with a gene therapy target for heart failure and work on a way to inhibit that process,” says Dr. Mark Mercola, professor in the Development, Aging and Regeneration Program at Sanford-Burnham and professor of bioengineering at UC San Diego Jacobs School of Engineering. “The results of this study validate our approach to identifying microRNAs as potential therapeutic targets with significant clinical value.”

Mercola’s laboratory has pioneered the use of robotic high-throughput methods of drug discovery to identify new targets for heart failure. The researchers used high-throughput robotics to sift through the entire genome for microRNAs involved in heart muscle dysfunction. They developed a commercial instrument now marketed by Vala Sciences of San Diego.

Then the researchers at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai found that injecting a small piece of RNA to inhibit the effects of miR-25 dramatically halted heart failure progression in mice. In addition, it also improved their cardiac function and survival.

Hajjar explains that heart failure is the endpoint of many things—heart attacks that damage muscle, damaged valves, untreated hypertension and genetic factors in the family history. “Currently, heart failure medications do not effectively address the underlying mechanisms that weaken contractile function and lead to the enlargement of heart muscle cells,” he says.

“Our study provides us with the key evidence we need to begin developing miR-25 as an important new therapeutic target, while adding our successful technique to block this microRNA to our growing arsenal of promising heart failure therapies that we will further develop and test in future clinical trials,” he adds. “After experiments are done in rodents, we will do them in larger animals. When we have validation, we will want to develop a treatment modality.”

Currently, Hajjar’s laboratory is developing novel gene therapies for patients with heart failure. One therapy, currently in phase 2b/3 human clinical trials, uses a modified viral vector to deliver a gene that produces SERCA2a, an enzyme found in healthy heart muscle cells. Another therapy, in preclinical development, uses a disabled virus to deliver a gene called SUMO-1, which shrinks enlarged heart muscle cells and improves cardiac function.

“With new therapeutic targets for heart failure, the commercial potential is huge,” Mercola notes. “With the paucity of new targets and the high cost of clinical trials, some pharmaceutical companies had decided to get out of the cardiovascular space. Some have come back. Now we hope to improve the quality of life for people with heart failure. We want to be able to use what we know to combat that insidious disease and push someone’s heart back to improved function.”