Gene therapy has prompted patients with hopelessly blocked blood vessels in their legs to grow their own bypasses.
Most patients in a small study saw a dramatic reversal of the predictably downhill course of that type of cardiovascular disease.
The results, reported Sunday at the scientific meeting of the American Heart Association in Orlando, Fla., by Dr. Jeffrey Isner of St. Elizabeth’s Hospital and the Tufts University School of Medicine near Boston, covered 10 patients. Although that is not a large number, some experts said the study was a rare demonstration of a clinical benefit from gene therapy and might be pivotal.
Isner and his colleagues injected genes into legs, eliciting the growth of a web of hairlike blood vessels that rerouted blood around the blockages and could be seen with X-ray and magnetic resonance imaging.
As a result, he reported, three patients who had been scheduled for amputations avoided them entirely because blood flow improved so markedly. For six other patients, severe and unrelenting pain lessened; two of them, who had been scheduled to lose legs, each lost a toe to amputation. In some cases, gangrene cleared up. Only one of the 10 patients failed to respond.
A paper describing the results has been accepted for publication in the journal Circulation, Isner said.
In addition to using a small number of patients, the study lacked a group that received a placebo for purposes of comparison. Medical experts urged that the work be repeated in a large study with such controls.
Until then, said Dr. R. Sanford Williams, chief of cardiology at the University of Texas Southwestern School of Medicine in Dallas, “we have to be extremely cautious and avoid giving false hope.”
Nonetheless, some experts said, the results were compelling. The patients, after all, were in the final stages of a devastating disease. There was essentially no chance that their conditions would improve on their own. And never before, some experts said, had gene therapy resulted in the clinical improvement of a disease.
“This could be a pivotal study,” said Dr. James Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania.
Dr. Stuart Orkin, a professor of pediatric medicine at the Harvard Medical School, said, “It is one of the first, if not the first, times that gene therapy has resulted in a clinical improvement.”
Orkin is co-chairman of a committee convened by Dr. Harold Varmus, director of the National Institutes of Health, to advise him on gene therapy research.
And despite his trepidation about giving false hope, Williams said, he found the results thrilling. In fact, he added, when some of the patients’ histories are described, “you have to say, ‘Wow.”’
Each year 30,000 to 40,000 Americans develop such severe blockages in their leg arteries that they have excruciating pain or ulcers on their legs that do not heal. Those patients, unlike people with blocked coronary arteries, cannot be treated with drugs, because none are effective for their condition.
Instead, they face eventual amputations, as the lack of blood flow leads to infections and gangrene. But amputations are very risky.
Isner said that 20 percent of those patients died in the hospital and that 40 percent died within a year of the surgery. His patients, Isner said, had the most to gain and the least to lose from gene therapy.
The study exploited the remarkable properties of a gene known as the vascular endothelial growth factor, or vegF, that is thought to be the body’s signal to grow new blood vessels.
The idea was to inject vegF genes into muscle cells near the blockage and allow the muscles to take up the gene and use it to make vegF protein. About 5 percent of the billions of genes that Isner injected actually went into muscle cells and were used by them.
Upon taking up the genes, the muscle cells secreted the vegF protein, which made its way to nearby blood vessels.
Normally, vegF would not avidly attach itself to cells that line the blood-vessel walls. But when a vessel is blocked, the cells just beyond the blockage, which are starved for blood, become very sticky for vegF. And so the vegF proteins presumably attached themselves to the exact sections of the blood vessels where they were needed.
With vegF stuck to their surfaces, the cells started to sprout a network of threadlike blood vessels. When that happens, for reasons that are still mysterious to researchers, the new vessels wind their way around the blockage and form an alternative pathway for blood.
Any vegF that did not attach to cells near the blockage was swept away by the bloodstream and degraded. The muscle cells secreted vegF only for several weeks, just long enough for the body to grow its bypasses.
“When we began our study,” Isner said, “we had no idea what dose of gene therapy was going to work or if the way we were injecting the genes was appropriate or if the sites we were injecting were appropriate. I have to admit, we really lucked out.”