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DURHAM, N.C. -- Early intervention with a novel kind of
"smart gene therapy" might effectively prevent the organ damage
commonly suffered by heart attack victims, suggests a new
animal study by researchers at Brigham and Women's Hospital in
Boston and Duke University Medical Center. The therapy combines
a therapeutic gene with a genetic "sensor" that recognizes and
responds to the oxygen deprivation that follows the reduced
blood flow, or ischemia, from coronary artery disease and heart
attack.

As soon as the oxygen declines, the sensor turns on the
therapeutic gene, thereby protecting the heart. In addition to
its potential for patients with heart disease, the strategy
might also prove useful for any condition in which tissues are
susceptible to loss of blood supply, including stroke, shock,
trauma and sepsis, the researchers said.

When administered to rat hearts several weeks before
ischemia, the designer gene combination protected the heart
from much of the damage that may weaken the organ and lead to
failure, according to the researchers. Their report will appear
in a forthcoming issue of Proceedings of the National Academy of
Sciences and in the journal's online edition the week of
Aug. 2, 2004.

The finding marks the first time a therapeutic gene complete
with a built-in sensor that allows the gene to respond
immediately to the condition it treats has been shown to work,
said Victor J. Dzau, M.D., chancellor of health affairs at Duke
University and an active physician-scientist at Duke. Such a
therapy could offer a significant advance over available
methods for treating heart patients, which are limited in their
ability to provide treatment in the narrow window of time
before irreversible heart damage occurs, he said. The work, led
by Dzau at Brigham and Women's Hospital prior to his move to
Duke in July, was supported by the National Institutes of
Health and the Edna Mandel Foundation.

"While drugs that can protect heart muscle are available,
most patients barely make it to the hospital in time to take
advantage of them," Dzau said. "This smart gene therapy could
be administered preemptively to high- risk patients months
before they develop a heart attack to provide them with
long-term protection from ischemic injury. The minute this gene
is switched on following a loss of blood flow, levels of the
therapeutic protein rise rapidly, providing near-complete
protection."

In patients with myocardial ischemia, the loss of blood flow
causes the heart tissue to slowly or suddenly starve of oxygen
and other nutrients. Eventually, said Dzau "little bits of
heart muscle get chewed away" as tissue dies, weakening the
organ and resulting in failure. When blood flow becomes blocked
completely, a heart attack can ensue. Physicians may be able to
reopen narrow or blocked heart vessels with balloon
angioplasty, but delayed restoration of blood flow often leads
to inflammation and tissue injury. Ischemia also can occur in
arteries of the kidneys, lungs, liver or the brain, where it
leads to stroke, he added.

The team developed a "therapeutic gene construct" that
contains both DNA sequences that can detect oxygen deficiency
and a therapeutic human gene -- heme-oxygenase 1 -- that has
been shown to protect cells. They then inserted the gene
construct into a harmless virus known as adeno-associated
virus, whose job was to transport the therapeutic gene into the
genetic material of the rat's cells.

"We're trying to create a physiological on-off switch that
will automatically turn on the therapeutic gene when ischemia
causes dangerous levels of oxygen deprivation," Dzau said.
"Such internal regulation is ideal for safe and effective gene
therapy."

The researchers injected the gene construct into the heart,
liver and skeletal muscle of rats in the laboratory. Five weeks
later, they restricted blood flow to the animals' organs by
clamping key arteries for a period of an hour and then
examining the organs for evidence of injury.

Inducing ischemia and oxygen deprivation in this way caused
a five-fold increase in the therapeutic gene's activity in the
heart, the researchers reported. That activity, in turn,
resulted in a dramatic reduction in damage to the heart, Dzau
said, with a significant 65 percent decrease in tissue death in
animals treated with the gene construct compared to control
animals. Skeletal muscle and liver exhibited a similar decline
in injury following the gene therapy treatment.

In addition, one month later the untreated animals exhibited
severe thinning of the heart wall and reduced heart function
compared to those that received the gene therapy. After four
months, the untreated rats still showed marked thinning of the
heart wall, while those treated with the gene construct showed
virtually no evidence of damage, Dzau said.

The team will next verify its results in another large
animal model. If the findings hold, Dzau predicts the therapy
might be ready to enter a phase I clinical trial in human
patients in as little as a year. The adeno-associated vector
used to insert the gene construct has been shown to be safe for
humans through its use in the treatment of hemophilia, noted
Dzau.

Collaborators on the research include Alok Pachori, lead
author of the study, Luis Melo, Melanie Hart, Nicholas Noiseux,
Lunan Zhang, Fulvio Morello, Scott Solomon, Gregory Stahl and
Richard Pratt, all of Brigham and Women's Hospital.