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DURHAM, N.C. -- The term "heart surgery" usually conjures
images of scalpels and sutures, but a new generation of
molecular surgeons at Duke University Medical Center is
operating with genes to fix ailing hearts.

A team of Duke heart surgeons and molecular biologists is
leading an interdisciplinary effort to treat congestive heart
failure with gene therapy, insertion of genes into heart cells
to repair damaged heart muscle. Traditional treatments for
heart failure include drug regimens and physical therapy, and,
as a last resort, a heart transplant, but the condition still
claims more than 40,000 lives per year.

Walter Koch, an assistant professor of experimental surgery,
and his colleagues are bypassing conventional methods and have
shown in a series of recent studies that a new class of
DNA-based therapies may stop progression of heart failure in
animals.

Koch, Robert Lefkowitz, a cardiologist, biochemist, and
Howard Hughes Medical Institute investigator, and postdoctoral
fellow Karsten Peppel detail their progress in the July issue
of Trends in Cardiovascular Medicine.

"The concept of gene therapy to treat heart failure is built
upon years of research to identify the molecular components
responsible for maintaining contraction of the heart muscle,"
said Koch, lead investigator of the studies. "Both we and other
researchers have identified protein products of genes that can
enhance the function of failing hearts. Our task now is to
deliver those genes in the right amount to the failing hearts
to improve function, but without compromising other
organs."

In congestive heart failure, the heart muscle loses it
ability to stretch and contract, usually due to clogged
arteries caused by coronary artery disease. The pumping
chambers often do not completely fill with blood between
strokes, causing poor circulation that deprives organs of
adequate oxygen and nutrients. 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, costing more than $10 billion
annually.

The syndrome is notoriously difficult to treat, although
early symptoms are often mild, and can be modulated with
changes in diet and exercise. But as the disease progresses,
less and less can be done. As the heart tries to compensate, it
pumps faster and increases its bulk to pump harder. This leads
to an enlarged heart. The additional muscle mass can harden the
heart walls and hamper rather than bolster the pumping
action.

Another of the body's responses to heart failure is
increased production and release of the stress hormone
norepinephrine, which binds to beta adrenergic receptors (bARs)
present on heart cells. This stimulation initially helps the
heart beat faster and more powerfully, but it quickly becomes
self-defeating: the norepinephrine-stimulated receptors become
desensitized by a second molecule called b-adrenergic receptor
kinase (bARK), Lefkowitz, Koch and their colleagues showed.

A series of studies in mice helped the researchers identify
strategies to boost heart function using the body's own
proteins instead of drug therapies.

Lefkowitz and his colleagues demonstrated in 1994 that mice
genetically altered to produce excess bARs have supercharged
hearts that beat faster and stronger than normal mice. As
reported in the April 24, 1994, issue of the journal Science,
these mice mimicked normal animals treated with the human heart
failure drug dobutamine, but without the use of any drugs.

Conversely, in the June 2, 1995, issue of Science the
researchers reported on genetically altered mice that produce
too much bARK in their hearts. These mice mimic aspects of
congestive heart failure in people. When the researchers
injected a synthetic adrenaline-like hormone into these mice,
the animals couldn't contract their heart muscles as well or
increase their heart rate as much as normal mice. The
transgenic mice displayed a lack of hormone response similar to
that seen in patients with heart failure, the researchers said.
This study suggested that too much bARK could cause heart
dysfunction by greatly diminishing the heart's ability to
respond to hormone signals to contract.

"These experiments demonstrated for the first time in living
animals that too much bARK hinders heart function," Lefkowitz
said in an interview. "This is a potentially significant
advance in our understanding of heart failure because
stimulation of adrenergic receptors is the final, common
pathway that is impaired in all cases of heart failure no
matter what the cause. If we could reverse this deficiency, we
may be able to improve the outcome for patients with heart
failure."

Once the Duke researchers were convinced that increased
levels of bARK lessen the ability of the heart to respond to
hormones, they wondered whether, if they blocked bARK, would
they restore heart function?

Koch reasoned that if it was possible to block bARK from
shutting down the heart's bARs, heart function might be
boosted. He designed a molecule that blocks bARK and created a
mouse model that introduced this protein inhibitor into the
mouse hearts. The inhibitor actually competes with the normal
bARK 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. "We are
now using these two strategies: increasing the number of bARs
and inhibiting bARK to rescue failing hearts in animals."

Koch and the gene transfer team, which also includes Dr.
Donald Glower, a heart surgeon, and surgical fellows Dr. R.
Eric Lilly and Dr. Alan Kypson, is now studying methods of gene
transfer in rats and rabbits to deliver these therapeutic
genes.

In their review article the researchers outline the ideal
gene transfer technology. They say it should:

Ensure long-term production of the desired protein product;
Be made only in the heart; Cause few side effects; Be minimally
invasive.

In recent years researchers at Duke and other institutions
have made progress on several fronts.

They first assessed whether genes could be delivered by
adenovirus, the common cold virus. Researchers modified the
virus or "vector," to carry therapeutic genes into rabbit cells
in culture. The researchers ensure genes are turned on only in
the heart by putting them under the control of genetic switches
that are turned on only in the heart. These studies, published
in the January 1997 Journal of Clinical Investigation, showed
that the bARK inhibitor kept heart cells sensitive to hormone
stimulation when normal heart cells would have become
desensitized.

The researchers then used a balloon catheter similar to the
ones used in opening blocked arteries in people to inject the
vector 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 the heart cells made the protein product.
Unfortunately, the cells only make the protein product for a
short time.

"We are operating under the same limitations as researchers
experimenting with gene therapy for other medical conditions,"
Koch said. "The vectors currently in use that carry DNA into
cells have side effects such as inflammation caused by an
immune response to the vector. We are concentrating on
developing our gene delivery techniques and continuing to
identify candidate therapeutic genes so that when the right
vector comes along, we will be ready."

Koch emphasizes that a new generation of gene transfer
vectors such as the cold virus will need to be developed before
gene therapy for heart failure becomes practical. But once that
hurdle is overcome, Koch's animal and cell culture studies
indicate gene therapy for heart failure may become a practical
option.

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Koch is available for interviews at (919) 684-3007.