Heart researchers have used gene therapy to bring failing rat hearts back to normal

Dec 4 2004

Heart researchers at Jefferson Medical College have used gene therapy to bring failing rat hearts back to normal.

Scientists led by Walter Koch, Ph.D., director of the Center for Translational Medicine in the Department of Medicine in Jefferson Medical College of Thomas Jefferson University in Philadelphia, used a virus to insert the gene for a protein called S100A1 into failing rat hearts.

“In contrast to other gene therapy strategies geared to overexpressing a gene,” says Dr. Koch, who is W.W. Smith Professor of Medicine at Jefferson Medical College, “because this protein is reduced in heart failure, simply bringing the protein level back to normal restored heart function.” Dr. Koch and his co-workers report their findings December 1, 2004 in the Journal of Clinical Investigation.

S100A1, which is part of a larger family of proteins called S100, binds to calcium and is primarily found at high levels in muscle, particularly the heart. Previous studies by other researchers showed that the protein was reduced by as much as 50 percent in patients with heart failure. A few years ago, Dr. Koch and his co-workers put the human gene that makes S100A1 into a mouse, and found a resulting increase in contractile function of the heart cell. The mice hearts worked better and had stronger beats.

Dr. Koch’s Jefferson team now examined whether it could make failing hearts normal again. The researchers – 12 weeks after they simulated a heart attack in the rats – delivered the human S100A1 gene to the heart through the coronary arteries by injection of a genetically-modified common cold virus as a carrier. After about a week, they found the hearts began to work normally. In addition, the animals’ heart muscle showed improved efficiency in using its energy supply, which was decreased in heart failure. According to Dr. Koch, the improvements were seen in both the whole animal as well as in individual heart cells.

“This is one of the first studies to do intracoronary gene delivery in a post-infarcted failing heart,” he says. “This proves it could actually be a therapy since most of the previous studies of this type are aimed at prevention – giving a gene and showing that certain heart problems are prevented. In those cases, heart problems are not actually reversed. This is a remarkable rescue and reversal of cardiac dysfunction, with obvious clinical implications for future heart failure therapy.”

Close to 5 million Americans have heart failure and more than 400,000 new cases are being diagnosed each year. While the overall death toll from heart disease has declined, the number of people dying from chronic heart failure continues to rise. For example, the death rate from coronary heart disease dropped 49 percent between 1970 and 1990, while deaths due to heart failure increased 64 percent over that period.

“We have a unique molecule necessary for normal heart function,” Dr. Koch says, noting that animals lacking the gene for S100A1 are seemingly healthy until they are subjected to cardiac stress, after which they usually die. The animals in the current study that received the gene transfer were fine.

Next, he and his colleagues hope to learn more about the mechanisms behind S100A1’s actions, and eventually, develop gene therapy protocols in humans. S100A1 is also found in the cell’s energy-producing mitochondria, he notes. He thinks the protein may be a link between energy production and calcium signaling in the heart cell – a crucial part of the process that makes the heart beat.