Promising new drug target discovered for treatment and prevention of heart failure

August 27, 2012, European Society of Cardiology

A promising new drug target for the treatment and prevention of heart failure has been discovered by researchers at Mount Sinai School of Medicine in New York, NY, US. The study was presented at the ESC Congress 2012 by principal investigator Professor Roger J. Hajjar, MD.

According to the US Centers for Disease Control and Prevention, about 5.8 million Americans suffer from heart failure and 670,000 new cases are diagnosed each year. One in five people with heart failure die within one year of diagnosis. Heart failure is most often treated with aggressive medical and device therapy, but has no cure. The most common symptoms of heart failure are shortness of breath, feeling tired, and swelling in the ankles, feet, legs, and sometimes the abdomen.

In this study presented at the ESC Congress 2012, researchers identified a new that may treat and/or prevent heart failure. The team evaluated failing human and pig hearts and discovered that SUMO1 (small ubiquitin-like modifier), a small protein that regulates the activity of key transporter genes, was decreased in failing hearts. When the researchers injected SUMO1 into these hearts via gene therapy, was significantly improved.

"This indicates that SUMO1 may play a critical role in the pathogenesis of heart failure," said Professor Hajjar, who is research director of Mount Sinai's Wiener Family Laboratories.

Led by Professor Hajjar, the team has been evaluating the transporter gene SERCA2a in patients with severe heart failure as part of the CUPID (Calcium Up-regulation by Percutaneous administration of gene therapy In ) trial. When delivered via an adeno-associated —an inactive virus that acts as a medication transporter—into , SERCA2a demonstrated improvement or stabilisation with minimal side effects. But Professor Hajjar said: "We found that while injection with SERCA2a restored cardiac function, over time the new SERCA2a became dysfunctional. This indicated that something else upstream from SERCA2a was causing the dysfunction in the heart."

Dr Changwon Kho, PhD, and Dr Ah Young Lee, PhD, two experts in the study of cardiac proteins at Mount Sinai School of Medicine, identified SUMO1 as the regulator of SERCA2a, showing that it enhanced its function and improved its stability and enzyme activity. When Professor Hajjar and his team studied human and animal models, they found that when SUMO1 was decreased, SERCA2a became dysfunctional in human hearts, showing that SUMO1 plays a protective role. When the team injected SUMO1 as a gene therapy, they found that it protected SERCA2a from oxidative stresses that are prevalent in heart failure.

"Our experiments over the last four years beginning with the discovery of SUMO1 as an interacting protein of SERCA2a have shown that it plays a critical role in the development of heart failure," said Professor Hajjar. "In fact, SUMO1 may be a therapeutic target at the earliest signs of development and may be beneficial in preventing its progression, a much needed advance for the millions suffering from this disease."

Dr Lisa Tilemann extended the experiments performed in mice and rats in a preclinical model of heart failure in porcine models.

Professor Hajjar said: "We have now clearly shown that SUMO1 gene delivery can enhance cardiac function and stabilize the deteriorations of left ventricular volumes in large animals with severe heart failure. We have also shown that delivering SUMO1 and SERCA2a concomitantly can have synergistic benefits on overall function in heart failure."

Led by Professor Hajjar, the Mount Sinai team discovered the landmark potential of SERCA2a in 1999 and since then has been pursuing its potential as a treatment delivered via gene therapy. The next stages in the research include testing a novel gene therapy construct which will combine both SUMO1 and SERCA2a within one gene therapy vector that will enable the investigators to express both genes simultaneously. Similar to their efforts in the CUPID trial they will explore the delivery of SERCA2a and SUMO1 via . Additionally, the research team has developed a cellular test to screen for compounds that may increase the interaction of SERCA2a with SUMO1, evaluating SUMO1 as an adjunctive therapy to SERCA2a.

Professor Hajjar concluded: "While this study re-affirms the importance of SERCA2a as a target in heart failure, our discovery of the critical role that SUMO1 plays in improving SERCA2a function in heart failure will hopefully lead to novel treatment strategies for patients with ."

Explore further: Promising target in treating and preventing the progression of heart failure identified

Related Stories

Promising target in treating and preventing the progression of heart failure identified

September 7, 2011
Researchers at Mount Sinai School of Medicine have identified a new drug target that may treat and/or prevent heart failure. The team evaluated failing human and pig hearts and discovered that SUMO1, a so-called "chaperone" ...

Researchers develop new gene therapy for heart failure

June 28, 2011
Researchers at Mount Sinai School of Medicine have found in a Phase II trial that a gene therapy developed at Mount Sinai stabilized or improved cardiac function in people with severe heart failure. Patients receiving a high ...

Recommended for you

Starting periods before age of 12 linked to heightened risk of heart disease and stroke

January 15, 2018
Starting periods early—before the age of 12—is linked to a heightened risk of heart disease and stroke in later life, suggests an analysis of data from the UK Biobank study, published online in the journal Heart.

'Decorated' stem cells could offer targeted heart repair

January 10, 2018
Although cardiac stem cell therapy is a promising treatment for heart attack patients, directing the cells to the site of an injury - and getting them to stay there - remains challenging. In a new pilot study using an animal ...

Two simple tests could help to pinpoint cause of stroke

January 10, 2018
Detecting the cause of the deadliest form of stroke could be improved by a simple blood test added alongside a routine brain scan, research suggests.

Exercise is good for the heart, high blood pressure is bad—researchers find out why

January 10, 2018
When the heart is put under stress during exercise, it is considered healthy. Yet stress due to high blood pressure is bad for the heart. Why? And is this always the case? Researchers of the German Centre for Cardiovascular ...

Heart-muscle patches made with human cells improve heart attack recovery

January 10, 2018
Large, human cardiac-muscle patches created in the lab have been tested, for the first time, on large animals in a heart attack model. This clinically relevant approach showed that the patches significantly improved recovery ...

Place of residence linked to heart failure risk

January 9, 2018
Location. Location. Location.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.