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Angiogenesis Therapy Successful for Peripheral Arterial Disease

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Duke Health News 919-660-1306

DURHAM, N.C. – Duke University Medical Center researchers
have shown that they can stimulate the body to produce its own
naturally occurring growth factors to promote blood vessel
growth into tissue damaged by peripheral arterial obstructive
disease (PAOD). They said their finding could offer a new
approach to treating the disease, which rivals coronary artery
disease in its prevalence and health impact.

The researchers injected into rabbits with a version of PAOD
a gene-carrying molecule, called a plasmid, which carried a
gene that is the blueprint for a protein known as the
"zinc-finger-activating" (ZFP) transcription factor.
Transcription factors are proteins that switch on other
genes.

In the rabbits, the gene produced ZFP transcription factor
that successfully activated a key blood-vessel-growth gene,
called VEGF, whose protein product triggers blood vessel
growth, found the researchers.

Importantly, the researchers demonstrated that this plasmid
stimulated the production of three different forms of VEGF,
much as the body would on its own. The researchers said they
believe that the latest finding is an important advance in the
field of therapeutic angiogenesis -- the process of blood
vessel growth -- because past studies of VEGF in humans have
only involved one form of VEGF and have seen only limited
success..

In addition to stimulating new vessel growth and improving
perfusion in the damaged leg tissue, the treatment also
appeared to prevent the programmed cell death, known as
apoptosis, of muscle cells starved of blood supply but not yet
dead, the researchers reported.

The results of the Duke study, led by cardiologist Brian
Annex, M.D., are scheduled to be published in the Oct. 19,
2004, issue of the journal Circulation, and are available
on-line at http://circ.ahajournals.org/.

"Peripheral arterial obstructive disease, which has a
national incidence approaching that of coronary artery disease,
is a major health care issue for which there are few effective
remedies," Annex said. "This new agent may provide a novel and
effective approach to treating a disease that can be just as
debilitating as coronary artery disease."

The National Institutes of Health (NIH) has just begun a
clinical trial using the plasmid, and Duke will also initiate a
similar clinical trial in the coming months.

It is estimated between 8 to 12 million Americans suffer
from PAOD. In mild cases, known as intermittent claudication,
patients feel muscle pain upon exertion. More severe cases,
known as critical limb ischemia, can lead to gangrene or tissue
death, often necessitating amputation of the effected limb.
While there are drugs and invasive procedures for the disorder,
none are particularly effective, the researchers said.

VEGF, because of its ability to stimulate new blood vessel
growth, is a naturally occurring substance that has intrigued
scientists for years, said the Duke researchers. Cancer
specialists, for example, are looking at ways of blocking
VEGF-induced blood supply to tumors, while cardiologists are
attempting to harness its properties to replenish blood flow to
starving tissues throughout the body.

Earlier studies in mice had shown that the ZFP-carrying
plasmid could induce VEGF production and stimulate
angiogenesis, but the Duke study was the first one to show
efficacy in an ischemic model.

"While we've have limited success using VEGF for patients
with peripheral arterial disease, we feel that new approach
will have a better chance of succeeding," Annex said. "In
previous studies, only one form of the VEGF protein was used.
This new approach appears to give the body control over the
production of the amounts and types of VEGF that it needs."

For their experiments, the researchers induced limb ischemia
in the hind legs of rabbits. Ten days later, they injected the
plasmid into the effected legs. At regular intervals during the
next 32 days, the researchers measured the effects of treatment
and found that when compared to the non-treated legs, the
treated legs had an increase in capillary density, a positive
increase in cellular proliferation and improved tissue
perfusion.

Additionally, the researchers found significant increases in
the circulating levels of three forms of VEGF – VEGF-121,
VEGF-165, and VEGF-189.

"Each form varies in its affinity for binding to tissue and
may different effects," Annex explained. "VEGF-121, for
example, is fairly soluable, so when you inject it into the
leg, it travels throughout the body. This is the form used in
past human trials.

"VEGF-189, on the other hand, does not easily go into
circulation, so it stays where you put it," Annex continued.
"VEGF-165 is somewhere in the middle. However, what's most
important is that we saw elevated levels of all three, which
would indicate that the body was creating those forms in the
amounts it needed."

The researchers also found that the treatment appeared to
protect damaged cells from undergoing the process of
apoptosis.

"The results of these preclinical studies demonstrate for
the first time that stimulating innate VEGF gene expression
leads to the creation of multiple forms of VEGF that appear to
provide therapeutic angiogenesis," Annex said.

The study was supported by American Heart association, the
National Institutes of Health, and by an unrestricted grant
from Edwards Lifesciences, Inc., Irvine Calif. Annex has no
financial interest in Edwards Lifesciences.

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