Stanford researchers have devised a novel
approach for delivering a clot-busting gene to blocked leg arteries
in animals, effectively restoring blood flow to the damaged vessels,
according to a new study presented at the 24th scientific meeting of
the Society of Cardiovascular and Interventional Radiology.
The researchers inserted the gene for human tPA (tissue plasminogen
activator) into a healthy leg vein in rabbits. The vein began pumping
out large quantities of tPA, and then was used as a bypass for an
adjacent artery constricted by a blood clot. The procedure reduced
clotting by 75% and restored normal blood flow in the legs of treated
rabbits, said Michael Kuo, MD, a radiology resident at Stanford
University Medical Center and the first author of the study.
Creating Super Veins
Were taking a vein and making it into a super structure
that is resistant to clots, which are the number one killers in this
country, said Dr. Kuo, who presented the study.
Dr. Kuo said the technique could benefit the millions of patients
with peripheral vascular disease. As many as 5% of men and 2.5% of
women in the United States 60 years or older have symptoms of
peripheral vascular disease.
A current treatment for peripheral vascular disease involves
injecting tPA-like clot-busting drugs into the patients
bloodstream. However, one major drawback of this generalized
treatment is that it can induce serious bleeding in the body. This
new therapy would sidestep that problem by delivering the gene
directly to the site of the blockage.
Because its locally delivered, bleeding is virtually
nonexistent, said Dr. Kuo.
The new technique also has the potential to greatly improve the
results of coronary artery bypass surgeries, which often fail as a
result of arterial clotting. The artery is particularly prone to
clotting within a month of surgery; 10 years after surgery, half of
all bypass grafts fail as a result of accelerated plaque build-up
that is believed to be related to clotting, he said.
With our new therapy, were technically able to get rid of
both the short- and long-term problems, said Dr. Kuo.
Surgeons could easily adapt the technique to coronary bypass
procedures. Theoretically, all they would have to do is inject the
tPA gene into the patients saphenous vein before removing it
from the thigh. The procedure would then follow its standard course,
with doctors sewing this clot-resistant super vessel into the
patients chest to channel blood past the diseased artery, said
The researchers now are moving toward testing the gene in humans.
Animal Study Protocol
In their initial study, the researchers applied the new therapy in
rabbits with blocked leg arteries. Two groups of animals served as
controls, receiving either a simple saline solution or a different
gene. The researchers used an adenovirus to serve as a delivery
vehicle for the tPA gene. They inserted the gene into a disabled form
of the virus and then injected this newly engineered virus into the
femoral vein in the animals legs. The veins then began turning
out large quantities of tPA.
The researchers applied the therapy in healthy veins because these
vessels would be more likely to integrate the gene, said Dr. Kuo. In
arteries that are affected by clotting, the plaque forms a barrier to
tPA, making it difficult to deliver the gene. The new clot-resistant
veins were then transplanted to the site of the diseased arteries. In
animals that did not receive the tPA gene, the clot blocked more than
60% of the artery. In the treated animals, the clotting was reduced
to 15% of the artery, enough to keep blood flow completely clear,
said Dr. Kuo.
The treatment appears to alter the vein so that it becomes more like
an artery, capable of handling more circulatory pressure. These super
veins are much less likely to fail in the long run, he said.
Dr. Kuos colleagues in the study were Michael Dake, MD,
associate professor of radiology at Stanford and the principal
investigator; Jacob M. Waugh, MD, a research fellow in interventional
radiology at Stanford; EserYuksel, MD, clinical professor of plastic
surgery at Baylor College of Medicine; and Adam Weinfeld, a medical
student at Baylor College of Medicine.
The study was supported by Stanford with no outside funding.