Mar. 7, 2001 DURHAM, N.C. -- After previously demonstrating that they could use gene therapy to prevent heart damage in rabbits with congestive heart failure, Duke University Medical Center researchers have now gone one step further to use gene therapy to actually reverse the damage already done to the rabbits' heart tissue.
Also for the first time, the researchers reported they employed minimally invasive techniques to deliver the gene therapy, giving them hope that in the near future, the same approach could be viable in treating humans with heart failure, one of the most difficult groups of heart patients to treat.
The Duke team, led by Walter Koch, associate professor of experimental surgery, reported the latest advances in the March 6 issue of the journal Circulation.
"We inserted a gene for a protein that inhibits the action of a particular cardiac enzyme into a modified form of a common virus and delivered it directly into the heart of a rabbit with heart failure through its coronary circulation," Koch said. "One week after the therapy, the damage suffered by the heart cells was reversing.
"If our work continues to progress as it has, we anticipate being able to possibly test this approach in a certain group of patients within three years," Koch said. "We would likely try it first on severe heart failure patients in the hospital awaiting a heart transplant to see if we could reverse the dysfunctioning part of the heart -- sort of like a molecular assist device."
Heart failure is a debilitating and ultimately deadly heart condition characterized by the heart muscle's inability to stretch and contract properly, meaning that oxygen-rich blood is not sufficiently delivered throughout the body. It usually occurs as a result of coronary artery disease or a heart attack. Patients experience fatigue, weakness, and often cannot conduct everyday activities. To date, physicians can only treat symptoms.
The Duke researchers wanted to find a way to boost the ability of the heart to pump blood and in a series of experiments conducted throughout the 1990s, they identified two key molecules responsible for regulating the heart's pumping action.
As a natural response to a diseased heart, the body releases the hormone norepinephrine, also known as the "fight-or-flight" hormone, directly into the heart, causing it to beat up to five times faster than normal. While in the short-term, this improves the heart's pumping action, in the long run it leads to heart failure. Norepinephrine works by binding to molecules called beta adrenergic receptors (BARs) located on the surface of heart cells.
Over time, these over-excited receptors become desensitized to the effects of norepinephrine, largely due to the effects of a second molecule, beta-adrenergic receptor kinase (BARK), which in healthy hearts helps restore heart contractions to normal after norepinephrine stimulation. Higher than normal amounts of BARK are found in failing heart tissue in humans. The investigators attached the gene that produces a peptide (BARKct) that blocks the actions of BARK onto a modified adenovirus, the virus that causes the common cold. The adenovirus acts as the "transport vehicle" which "infects" heart cells, and in the process, drops off the new gene. Once in heart cells, the gene directs the production of BARKct. In the experiments, the virus did not cause inflammation or provoke an immune response, the researchers said.
"Last year, we demonstrated that if we delivered this gene at the same time as producing a heart attack, we could prevent and delay the heart from being damaged," Koch said. "In our latestseries of experiments, we delivered the BARKct gene three weeks after a heart attack, and one week later, the damaged heart cells were returning to normal function. We began to reverse the heart damage in rabbits."
For Koch, the ability to deliver the gene therapy noninvasively is as significant as the effectiveness of the delivered gene, known as a transgene. The experiments used a catheter-based system, much like that used routinely on humans. Currently, the only clinical trials using gene therapy for heart diseases involves the use of growth factors that stimulate the creation of new blood vessels. However, this therapy is delivered directly to the heart muscle during open heart surgery, such as coronary bypass surgery.
"In the case of patients with heart failure, most are too sick to be able to withstand the rigors of a major surgery," Koch explained. "We already know that even very sick patients can safely undergo catheter-based procedures, so it would be an effective and safe way to deliver the therapy."
For their experiments, the researchers delivered the BARKct transgene through a catheter positioned in the coronary artery that supplies blood to the left ventricle, the heart chamber responsible for pumping newly oxygenated blood throughout the body. The right ventricle did not receive the gene therapy, in effect acting as a control. After one week, the researchers performed detailed analysis of the two chambers and found that the treated chamber had enhanced function towards normal levels, while the right ventricle continued to be in a state of failure.
The current adenovirus vector remained viable in the rabbit for about three to four weeks, Koch said, adding that an important area of continued research is the development of vectors that will permit longer expression of the gene. However, at least initially in those severely ill patients, a month or two of "molecular" support could keep heart failure patients alive long enough to receive a human transplant.
The choice of possible viral vectors for heart failure, however, is limited, mainly because heart cells, also known as myocytes, do not divide. In some gene therapy experiments for cancer, for example, researchers use retrovirus vectors, which allows the therapeutic genetic material to be inserted into the target cell, and then all subsequent generations of that cell will carry the new gene. Since myocytes do not divide, the researchers must "infect" as many myocytes as possible to achieve a therapeutic effect.
Now that the researchers have proven the principle of gene therapy for heart failure in such animal models as mice, rats and rabbits, they are now testing their approach in porcine models before moving on to human trials.
These findings also open the possibility of delivering transgenes to different target cells in the heart to treat other heart ailments, such as those that regulate calcium and potassium channels. "Levels of BARK are elevated in patients with many forms of heart disease, so our hypothesis is that it is a critical molecule in heart dysfunction," Koch said. "That makes not only an exciting target for gene therapy, but also a potential target for a pharmaceutical-based approach."
Members of the Duke research team included Dr. Ashish Shah, Dr. David White, Dr.Sitaram Emani, Dr. Alan Kypson, Dr. R. Eric Lilly, Katrina Wilson, Dr. Donald Glower and Dr. Robert Lefkowitz, a Howard Hughes Medical Institute investigator.
The Duke investigators are supported by grants from the National Heart, Lung, Blood Institute, part of the federal National Institutes of Health, and the American Heart Association.
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