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DALLAS, TX – Scientists are one step closer to making gene
therapy for heart failure a reality, scientists from Duke
University Medical Center reported Sunday.

Molecular biologist Walter J. Koch and his colleagues said
in a report prepared for the 71st scientific sessions of the
American Heart Association
that they have for the first time delivered therapeutic genes
throughout a rabbit's heart and have shown that the genes can
increase heart function.

The animal experiments are a crucial step in developing a
genetic treatment for congestive heart failure, a debilitating
and deadly condition in which heart muscle loses its 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 an inability to carry
out routine daily tasks. Right now, there is no effective means
to reverse heart failure, only to treat symptoms.

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

Koch, an associate professor of experimental surgery, and
his colleagues have been working for several years to find ways
to efficiently deliver genes to the heart to boost heart
function.

Early experiments focused on identifying the molecular
players that are responsible for efficient pumping action in
the heart and showing which ones aren't doing their jobs in
failing hearts. Using mouse models and sophisticated genetic
techniques, the Duke scientists showed that two key proteins in
heart cells work together to regulate heart function.

In diseased hearts, the body releases the hormone
norepinephrine, the "fight-or-flight" hormone, directly into
the heart, causing it to work up to five times harder than
normal. Norepinephrine binds to molecules called 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.
Desensitization is caused by a second molecule called
ß-adrenergic receptor kinase (ßARK), which in healthy hearts
helps restore heart contractions to normal after norepinephrine
stimulation. Studies subsequently showed that ßARK is elevated
in failing human heart tissue.

In 1994, Duke researchers showed that mice genetically
altered to produce excess beta adrenergic receptors (bARs) have
supercharged hearts that beat faster and stronger than a normal
mouse's heart. In 1997, the researchers inserted a gene that
encodes the bAR into an adenovirus, the same virus that causes
the common cold. When Koch and his colleagues allowed the virus
to infect isolated failing rabbit heart cells, the bAR gene
made up to 15 times the normal amount found in rabbit cells and
restored normal heart signaling.

"Our studies have shown that a malfunctioning beta
adrenergic receptor system leads directly to heart failure,"
Koch said. "By contrast, boosting levels of beta adrenergic
receptors or inhibiting ßARK can reverse heart failure in our
mouse genetic models. Now, we are beginning to see the same
result when we deliver these genes to rabbits."

The researchers used the results of the mouse studies to
design their latest gene therapy experiments in rabbits. They
increased the number of bARs by infusing a common cold virus
genetically engineered to contain the bAR gene into a living
rabbit's heart and allowing it to spread throughout the
coronary arteries. Then they measured the ability of the heart
to pump. Animals that received extra copies of bAR, which is
equivalent to 10 times the normal number of bARs on heart
cells, had significantly increased ability to pump,
demonstrated by a 20 percent increase in the force of the
heart's contraction.

The key to the researchers' success, Koch said, was using a
new surgical method to ensure that the adenovirus spread
throughout the heart. They injected the virus into the left
ventricle of live rabbits while the aorta was clamped for a few
seconds. This allowed the virus enough time to spread through
all the coronary vessels. Clamping the aorta is sometimes used
in human heart surgery, Koch said, making this gene delivery
method feasible.

In previous experiments, the researchers used a 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, but only in a limited area of heart
muscle.