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Gene Treatment can Boost Heart Function in Rabbits, Duke Researchers Say

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Duke Health News 919-660-1306

DURHAM, N.C. -- Scientists at Duke University Medical Center
have delivered therapeutic genes throughout a rabbit's heart
and have shown that the genes can both boost heart function on
their own and also increase sensitivity to heart-stimulating
drugs.

According to the researchers, the experiments, reported in
the July 1 Journal of Clinical
Investigation
, are a crucial step in developing a genetic
treatment for congestive heart failure. This debilitating and
deadly condition develops when 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. There is currently no effective
means to reverse heart failure, only to treat symptoms.

The research is funded by grants from the National
Institutes of Health and the American Heart Association
(AHA).

According to the AHA, about 400,000 new cases of congestive
heat failure 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.

Research team leader Walter J. 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.

In their experiments, the scientists first incorporated the
therapeutic genes into a live but disabled common cold virus.
Then, in a surgical technique that was a key to their success,
the scientists injected the virus into the left ventricle of
live rabbits while the aorta was clamped for a few seconds.
This technique allowed the virus enough time to spread through
all the coronary vessels to reach a majority of the heart
muscle. Clamping the aorta is sometimes used in human heart
surgery, Koch said, making this gene delivery method
feasible.

In the current experiments, the effect of the introduced
genes lasted for about three weeks. Koch said that he believes
the immune system eventually clears the adenovirus from the
body, eliminating the therapeutic effect. Koch emphasized that
more effective methods of carrying the genes into cells need to
be developed before gene therapy for heart failure in people
becomes a practical option. The researchers say that with the
development of improved viruses and other vehicles to introduce
genes into the heart, the technique might be used on congestive
heart failure patients within the next decade.

The latest achievement built on earlier basic studies in the
lab of Dr. Robert Lefkowitz, a Howard Hughes Medical Institute
investigator at Duke. Using mouse models and sophisticated
genetic techniques, Lefkowitz and his colleagues identified the
molecules responsible for fostering efficient pumping action in
the heart and showed which ones can make the heart function
more efficiently.

The Duke scientists showed that two key proteins in heart
cells - called beta-adrenergic receptors (þARs) and beta
adrenergic receptor kinase (þARK) -- work together to regulate
heart function. Receptors such as þAR are molecular switches
that turn on cell processes when triggered by external
substances such as hormones.

In reacting to a failing heart, the body releases large
amounts of the hormone norepinephrine directly into the heart.
This norepinephrine binds to þARs on the surface of heart
cells, triggering the heart to work up to five times harder
than normal. While this overstimulation initially allows the
heart to increase the power of its contractions, in heart
failure the stimulation quickly becomes self-defeating, because
the receptors become desensitized, meaning they no longer
respond to hormone stimulation.

This desensitization is caused by þARK, an enzyme inside the
cell that in healthy hearts helps restore normal heart
contractions after norepinephrine stimulation. In failing
hearts, however, þARK levels rise and the number of þARs is
greatly reduced.

In 1994, Lefkowitz, Koch and their colleagues showed that
mice genetically altered to produce excess beta adrenergic
receptors (þARs) have supercharged hearts that beat faster and
stronger than a normal mouse's heart. In 1997, the researchers
inserted a gene that encodes the þAR into an adenovirus.

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

In their earlier test tube experiments Koch and his
colleagues allowed the virus to infect isolated failing rabbit
heart cells. They found that the inserted þAR genes produced up
to 15 times the normal amount of the þAR protein found in
rabbit cells, which restored normal heart signaling. In the
current experiments, the animals' heart cells produced the
equivalent of 10 times the normal number of þARs. As a result,
they shows a 20 percent increase in the force of their heart
contractions.

In addition, the researchers tested the effects of a range
of concentrations of þARs and found that as they increased þAR,
they increased the force of contraction to a maximum of 20
percent.

The researchers tested whether the þARs would respond to the
drug isoproteronol, which stimulates þARs. When researchers
injected the drug into both normal rabbits and rabbits with the
additional þARs, they found the rabbit hearts with the
additional þARs responded to the drug even more so than the
normal rabbits.

"Our results with the isoproterenol challenge show that the
þARs we have inserted into the heart are functioning and
responding just like the native þAR," said Koch.

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