Failing Heart Cells Revived With Gene Therapy

October 22, 1997

DURHAM, N.C. -- Using a type of "molecular CPR," researchers at Duke University Medical Center have revived failing rabbit heart cells using the common cold virus genetically engineered to carry a human gene that restores normal pumping action.

Just as doctors use a defibrillator to restore a heart beat to patients whose heart muscle has lost a regular beat, Duke researchers have used genes known to regulate heart muscle contraction to revive flagging heart cells in laboratory vials. The successful gene therapy experiments point to a potential new drug target for treatment of heart failure in people.

The researchers, led by Walter Koch, an assistant professor of experimental surgery, report in the Oct. 28 issue of the Proceedings of the National Academy of Sciences that this new research suggests that DNA-based therapies can reverse heart failure in animals. The research was supported by grants from the National Institutes of Health and a National Research Service Award.

Duke heart surgeons and molecular biologists including Dr. Shahab Akhter, the paper's first author, Christine Skaer, Dr. Alan Kypson, Patricia McDonald, Karsten Peppel, Dr. Donald Glower and Dr. Robert Lefkowitz, a Howard Hughes Medical Institute investigator, are teaming up to treat congestive heart failure with gene therapy, insertion of genes into heart cells to repair damaged heart muscle.

In congestive heart failure, the heart muscle loses it ability to stretch and contract, usually due to clogged arteries caused by coronary artery disease. People with congestive heart failure often experience fatigue, weakness, and inability to carry out routine daily tasks.

According to the American Heart Association, about 400,000 new cases are recorded every year in the United States. Death rates from heart failure tripled between 1974 and 1994, making congestive heart failure the leading cause of hospitalization among people 65 and older and costing more than $10 billion a year.

In heart failure, the pumping chambers often do not completely fill with blood between strokes, causing poor circulation that deprives organs of adequate oxygen and nutrients.

The body responds to the stress on the heart by releasing the hormone norepinephrine, the "fight-or-flight" hormone that the body normally uses to prepare itself to handle a perceived threat. The brain releases norepinephrine directly into the heart, causing it to work up to five times harder than normal. Norepinephrine binds to beta adrenergic receptors (ßARs) present on heart cells. This stimulation initially allows the heart to increase the power of its contractions, but in heart failure it quickly becomes self-defeating: the receptors become desensitized, meaning they no longer are able to respond to hormone stimulation. Lefkowitz, Koch and their colleagues have shown that this desensitization is accomplished by a second molecule called ß-adrenergic receptor kinase (ßARK), which in healthy hearts helps restore heart contractions to normal after norepinephrine stimulation.

Koch reasoned that blocking ARK might boost heart function. In a June 2, 1995, issue of the journal Science, he described a mouse model in which he introduced a protein inhibitor of ARK into transgenic mouse hearts. The inhibitor actually competed with the normal ARK in heart cells, diluting its effect. The result was a transgenic mouse that had significantly enhanced pumping action and was very sensitive to the hormones that increase heart rate and contraction.

"These studies in transgenic mice were critical in identifying potential gene therapy targets," said Koch.

The researchers used the results of the mouse studies to design their latest gene therapy experiments in rabbits. They used a rabbit model of heart failure to test two strategies: increasing the number of ARs and inhibiting ARK.

"First we showed that the rabbit model of heart disease mimics human heart disease biochemically. For instance, levels of ARK were significantly elevated," Koch said. "Then we proceeded to insert the gene to attempt to correct the defect."

The researchers inserted a gene that encodes the ARK inhibitor into an adenovirus, the same virus that causes the common cold. When Koch and his colleagues allowed the virus to infect rabbit heart cells, the ARK inhibitor competed with the elevated ARK in failing heart cells, diluting its effect and restoring heart function.

"This is the first study to demonstrate definitively that gene transfer can rescue failing heart cells by restoring beta adrenergic function," said Koch.

In a second study, he and his colleagues inserted the gene for a ßAR into the cold virus and repeated the experiment. The additional receptors also boosted heart function.

In previous experiments, they used a balloon catheter similar to the ones used in opening blocked arteries in people to inject the virus into the coronary arteries, the arteries that feed the heart, in live rabbits. Using this method Koch and his colleagues demonstrated that they could get genes into heart muscle and that the heart cells made the appropriate protein product. They also found that, unfortunately, the cells only make the protein product for a short time.

The researchers are continuing experiments with a new generation of gene transfer agents such as the cold virus. But, he said, better gene therapy vectors need to be developed before gene therapy for heart failure becomes practical.

"The importance of this study is that we've shown inhibitors of ARK can reverse heart failure at the cellular level, without creating damage to the heart, like -agonist drug therapy does," Koch said. "Our mice that make the ARK inhibitor have a normal life span and don't have fibrosis, a common side effect of -agonist drugs such as isoproterenol. This should make ARK inhibitors an attractive target for drug discovery and therapy."

Duke University Medical Center

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