A currently popular ploy in the fight against solid tumors is to cut offtheir blood supply.
In this anti-angiogenesis strategy, the prime target is vascularepithelial growth factor, (VEGF), which promotes proliferation of theveins, arteries and capillaries that ferry nutrients to the growingcancers. (See BioWorld Today, Aug. 5, 1996, p. 1.)
Now a novel form of gene therapy is clinically testing the flip side ofangiogenesis, to see if VEGF can restore blood flow to blockedarteries in the legs.
Nearly two years ago, in September 1994, the National Institute ofHealth's Recombinant-DNA Advisory Committee (RAC), secondedby the FDA, authorized vascular surgeon Jeffrey Isner andbiomedical researcher Kenneth Walsh, of St. Elizabeth's MedicalCenter, in Boston, to treat peripheral artery disease by transferringthe cDNA gene for VEGF to the site of the blood blockage.
It remains the only gene therapy trial for this disorder of the 141protocols that the RAC has approved to date.
In the latest issue of The Lancet, dated Aug. 10, 1996, they report"Clinical evidence of angiogenesis after arterial gene transfer ofphVEGF165 in patient with ischemic limb."
That patient was a 71-year-old woman with gangrene of the right bigtoe. This is the farthest-out point in the body fed by the circulation.Multiple arteries between her knee joint and mid-leg were found tobe partly or completely choked.
Her toe's tissues, starved of blood, were moribund, and the twoadjacent digits showed signs of compromise as well.
Isner and his team constructed a plasmid to deliver the 165-amino-acid human VEGF gene to the site of the arterial occlusion, andcoated it onto the tip of a balloon angioplasty catheter. This slenderinflatable sealed tube is commonly used to clear atheroscleroticplaque from occluded blood vessels.
They threaded the balloon to the under-knee popliteal artery, and byinflating it transferred 2,000 micrograms of plasmid naked DNA tothat vessel.
Gene Transfer Worked, But Not Clinical Outcome
Four weeks later, imaging revealed "an increase in collateral [parallelarterial] vessels at the knee, mid-tibial and ankle levels, whichpersisted at a 12-week view."
Maximum blood flow to the limb went up by 72 percent over its pre-gene-transfer rate.
The slow-release VEGF gene continued for 21 days to expressvascular epithelial cells at the messenger RNA level.
But they also went so far as to generate three unwanted "spiderangiomas," _ benign vascular overgrows _ on the right foot. Thesurgeons removed one of these side effects; the two othersdisappeared on their own.
Despite these positive results, the Lancet paper reported, "limbgangrene could not be reversed, and the patient required below-kneeamputation five months after gene therapy."
The authors propose several possible reasons for the disappointingoutcome: They observe that this patient was the eighth in their genetherapy trial series since 1994, the first to show outgrowth ofcollaterals, and the first to receive a DNA dose of 2,000 micrograms.Previous recipients got smaller amounts, escalating from 100 and 500mg.
"If naked plasmid DNA alone is to be used [in future patients]," theysuggest, "then the optimum dose . . . remains to be established."
Repeated administration of the gene, they add, "e.g., three weeksafter the first dose" might enhance the "full maturation of a lengthycollateral network. The principal challenge now," they concluded, "isto optimize this strategy to achieve limb salvage."
Numerous laboratories are trying gene therapy preclinically inrabbits, dogs, pigs, guinea pigs and other animal models of arteriallimb disease. Isner and his colleagues perfected their approach overthe past several years in rabbits, with partial funding from theNational Heart, Lung and Blood Institute (NHLBI) of the NIH.
Results In Rabbits `Convincing'
At that agency, Constance Weinstein is leader of the CongenitalHeart Disease and Infectious Diseases Group, which manages grantsin the peripheral vascular area. "We have supported the basic scienceunderpinning of Isner's work, his studies in the rabbit and so on,which has been very convincing," said Weinstein.
She added that "there are various causes of limb ischemia, such assmoking. It seems to happen as people get older."
A recent survey by the National Center on Health Statistics countedsome 2.2 million Americans with "hardening of the arteries." But"this data on the prevalence of peripheral arterial disease is soft,"said NHLBI statistician Thomas Thom, who cited that figure.
He explained to BioWorld Today that it derived from homeinterviews rather than precise prevalence records. At the otherextreme, Thom added, is the number reported in 1993 of "265,000patients discharged from hospitals alive or dead with peripheralartery disease." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.