Failing Heart Cells Revived With Gene Therapy
DURHAM, N.C. -- Using a type of "molecular CPR," researchers
at Duke University Medical Center have revived failing rabbit
heart cells using the common cold virus genetically engineered
to carry a human gene that restores normal pumping action.
Just as doctors use a defibrillator to restore a heart beat
to patients whose heart muscle has lost a regular beat, Duke
researchers have used genes known to regulate heart muscle
contraction to revive flagging heart cells in laboratory vials.
The successful gene therapy experiments point to a potential
new drug target for treatment of heart failure in people.
The researchers, led by Walter Koch, an assistant professor
of experimental surgery, report in the Oct. 28 issue of the
Proceedings of the National Academy of Sciences that this new
research suggests that DNA-based therapies can reverse heart
failure in animals. The research was supported by grants from
the National Institutes of Health and a National Research
Duke heart surgeons and molecular biologists including Dr.
Shahab Akhter, the paper's first author, Christine Skaer, Dr.
Alan Kypson, Patricia McDonald, Karsten Peppel, Dr. Donald
Glower and Dr. Robert Lefkowitz, a Howard Hughes Medical
Institute investigator, are teaming up to treat congestive
heart failure with gene therapy, insertion of genes into heart
cells to repair damaged heart muscle.
In congestive heart failure, the heart muscle loses it
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 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 and costing more than $10 billion a
In heart failure, the pumping chambers often do not
completely fill with blood between strokes, causing poor
circulation that deprives organs of adequate oxygen and
The body responds to the stress on the heart by releasing
the hormone norepinephrine, the "fight-or-flight" hormone that
the body normally uses to prepare itself to handle a perceived
threat. The brain releases norepinephrine directly into the
heart, causing it to work up to five times harder than normal.
Norepinephrine binds to 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. Lefkowitz, Koch and their colleagues have
shown that this desensitization is accomplished by a second
molecule called ß-adrenergic receptor kinase (ßARK), which in
healthy hearts helps restore heart contractions to normal after
Koch reasoned that blocking ARK might boost heart function.
In a June 2, 1995, issue of the journal Science, he described a
mouse model in which he introduced a protein inhibitor of ARK
into transgenic mouse hearts. The inhibitor actually competed
with the normal ARK 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.
The researchers used the results of the mouse studies to
design their latest gene therapy experiments in rabbits. They
used a rabbit model of heart failure to test two strategies:
increasing the number of ARs and inhibiting ARK.
"First we showed that the rabbit model of heart disease
mimics human heart disease biochemically. For instance, levels
of ARK were significantly elevated," Koch said. "Then we
proceeded to insert the gene to attempt to correct the
The researchers inserted a gene that encodes the ARK
inhibitor into an adenovirus, the same virus that causes the
common cold. When Koch and his colleagues allowed the virus to
infect rabbit heart cells, the ARK inhibitor competed with the
elevated ARK in failing heart cells, diluting its effect and
restoring heart function.
"This is the first study to demonstrate definitively that
gene transfer can rescue failing heart cells by restoring beta
adrenergic function," said Koch.
In a second study, he and his colleagues inserted the gene
for a ßAR into the cold virus and repeated the experiment. The
additional receptors also boosted heart function.
In previous experiments, they used a balloon 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. They also found that, unfortunately, the cells
only make the protein product for a short time.
The researchers are continuing experiments with a new
generation of gene transfer agents such as the cold virus. But,
he said, better gene therapy vectors need to be developed
before gene therapy for heart failure becomes practical.