November 16, 2010

Studies Bring Gene Therapy to Treat Heart Failure Closer, say Thomas Jefferson University Researchers

Cardiology researchers at Thomas Jefferson University and the University of Heidelberg in Germany say they are close to testing two different gene therapy strategies aimed at reversing heart failure in patients.

At the annual meeting of the American Heart Association, scientists are presenting final laboratory and animal testing on these gene therapy treatments. The two teams have been working together for years on these novel approaches, says Walter Koch, Ph.D., director of the Center for Translational Medicine at Jefferson – the scientist who has spearheaded Jefferson’s development of gene therapy to treat heart failure. The gene therapy is produced at Jefferson and the animal studies are conducted in Germany.

Both potential gene therapies would be delivered by a catheter directly into a failing human heart through the coronary artery circulation, and both have shown ability to “rescue” heart failure in animal experiments. Jefferson researchers will also present two other associated studies.

“These findings are exciting, and we can’t wait to move forward,” says Dr. Koch.

Study in human heart cells taken from patients proves value of S100A1 gene therapy
The first study, to be presented at 11:45 a.m., CT, Monday, November 15, represents the last step needed before researchers seek Federal Food and Drug Administration (FDA) approval to conduct a study in patients with heart failure, says Dr. Koch.

All animal studies have been successful, and this laboratory study of human heart cells is the “final proof of principle,” he says.

This strategy involves using viral-mediated gene transfer to increase expression of a gene that makes a small calcium sensing protein, S100A1, that is normally highly expressed in the heart to help the heart muscle contract, but which is downregulated in heart failure. The Jefferson-Heidelberg research team has published more than a dozen research studies that demonstrates replacing S100A1 or bringing it back to normally expressed levels restores heart function, Dr. Koch says.

“We have shown this in mice, rats, and pigs, and this study demonstrates that the effect is the same when you restore S100A1 in cultured failing human ventricular myocytes in the laboratory,” he says.  These cells were isolated from diseased hearts removed from patients who were undergoing a heart transplant at Thomas Jefferson University Hospital.

“This proves that what we have seen in our animal studies is replicated in human heart cells,” he says. “It is our last step before human clinical trials.” Results will be presented by Henriette Brinks, M.D., a post-doctoral fellow working in the labs of Dr. Koch and also Patrick Most, M.D., who was until recently a faculty member at Jefferson’s Center for Translational Medicine and now is a Professor at the University of Heidelberg.

Inhibiting GRK2 rescues animal hearts that were failing
Another study, to be presented at 2:45 p.m., CT, Monday, November 15, shows that a second strategy works in pigs.

In this study, that was again a collaboration between Jefferson and the University of Heidelberg, the researchers tested use of a gene product known as the bARKct, which produces a peptide that inhibits GRK2, a G protein-coupled receptor kinase that is critically involved in normal and failing heart function. Dr. Koch, who has been studying GRK2 for two decades, had discovered that the enzyme is overexpressed after damage to the heart. He found that leads to progressive heart failure because GRK2 disrupts heart contractile function.

In this study, the researchers show that pigs with heart failure that received bARKct gene therapy had a 30 percent gain in heart function six weeks after the therapy.

“That is very significant,” Dr. Koch says. “The virus that we use to deliver bARKct genes just sits in heart cells and produces this peptide, blocking GRK2. The virus – and its beneficial therapy – lasts for a very long time.”

Koch expects to apply for FDA permission to conduct bARKct gene therapy in 2011.

The study is being presented by Phillip Raake, M.D., from the University of Heidelberg where he conducted these pre-clinical experiments with Dr. Most and Oliver Muller, M.D., also from the University of Heidelberg.

Rat study shows why tamping down GRK2 helps ailing hearts
A third study, being presented at 3:45 p.m., CT, Tuesday, November 16, furthers the understanding of why GRK2’s effect on myocytes (heart cells) after heart damage is pathologic.                        

A Jefferson University research team led by Dr. Koch has found that GRK2 overexpression changes the way myocytes use energy sources. Normal heart cells derive energy from metabolizing fatty acids, but when the heart is stressed, such as by exercise, these cells turn to glucose (sugar) because it produces energy more efficiently, which is what is needed when the heart is damaged.  This is done through the actions of insulin to increase the amount of glucose entering the heart cell.

The researchers discovered that when GRK2 is overproduced, damaged myocytes cannot switch from fatty acids to glucose due to a lack of insulin action. “A sick heart cannot change its metabolism to glucose and is stuck with using fatty acids,” says the study’s first author, Michele Ciccarelli, M.D., Ph.D., who is presenting the findings. “Fatty acid metabolism requires more oxygen than insulin metabolism does, so the heart is not able to produce enough energy and becomes quickly tired.”

Using rats, the researchers show that when GRK2 is inhibited by bARKct gene therapy, metabolism is significantly improved.

“Until now, therapies for heart failure have tried to improve the contractility of the heart,” Dr. Ciccarelli says.  “This shows that our approach of inhibiting GRK2 works differently, improving heart cell function in a substantial way.”

Exploring the use of cardiac stem cell therapy
At 3 p.m. CT, Monday, November 15, the Jefferson researchers will present a fourth study that explores the potential of engineering cardiac stem cells to repair a damaged heart.

Researchers know that cardiac stem cells have the potential to move out of bone marrow and travel to a heart and repair it after a heart attack. The Jefferson researchers hypothesize that beta-arrestin molecules working inside these stem cells regulate how the cells respond to chemicals released during a heart attack in order to grow and travel to the heart.                 

In this study done by the Koch Laboratory in the Center for Translational Medicine at Jefferson, led by researcher Mai Chen, MD, PhD, who will present the findings, the scientists conducted a variety of experiments to see what would occur if mice did not have one or both of their natural beta arrestin genes. They found that if they knocked out the genes, stem cells did not proliferate normally after heart damage and that weeks later, heart muscle had not regenerated in the same way that occurred in mice with the genes.

This suggests that beta arrestins are critical molecules in the normal bone marrow response to a heart attack, and that re-engineering stem cells to express more beta arrestins could possibly increase their potential to repair hearts, the researchers say.

These studies were funded by grants from the National Institutes of Health and the American Heart Association and also a gift from the George Zallie and Family Foundation.

Media Only Contact:
Richard Cushman
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 11/16/2010