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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."

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.

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.

A color image (shown below) is available as WalterKoch.1.jpg
in http://photo1.dukenews.duke.edu/pages/Duke_News_Service.