WASHINGTON — Peter Cummins lay still as doctors administered 20 injections into the 81-year-old’s calves and thighs, hoping the genetic experiment will spur new blood vessels to grow around his clogged leg arteries.
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The experiment at the National Institutes of Health marks a resurgence in attempts to get the body to grow its own bypasses, at first in the legs and, if that works, perhaps later in the heart.
It’s called therapeutic angiogenesis, a field that foundered a few years ago when early attempts proved disappointing. Now, a few companies are trying unique new approaches.
They’re in the first stages of human testing with no way yet to predict success. Specialists are intrigued, however, because the experiments are based on a much-needed better understanding of complex artery-controlling genes.
It’s an evolution that Dr. Brian Annex, Duke University’s angiogenesis research director, characterizes as going from hype to hope.
“There definitely is a renewed interest,” he said. This time around, “we’ve moved from the idea that this is an incredibly powerful magic bullet that you just have to have somewhere nearby and patients instantly get better. It was unrealistic to expect that.”
Blocked arteries increase heart risks
The body sometimes reroutes blood flow around blocked arteries, particularly during peripheral artery disease, or PAD, which afflicts at least 12 million Americans like Cummins, of Falls Church, Va.
Their leg arteries stiffen and narrow, slowly choking off blood flow to muscles until patients find walking difficult. Cummins, for example, can go only about two blocks before getting an aching pain called claudication. In more severe cases, PAD can lead to amputation. And having it quadruples the risk of a heart attack or stroke, because if leg arteries are clogged, other blood vessels probably are, too.
In the late 1990s, scientists tried injecting PAD patients with proteins called growth factors — the most famous was known as VEGF — involved in growth of new blood vessels.
That proved too simplistic: when new arteries grew, they tended to be weak and leaky. It turns out different types of growth factors — four forms of VEGF alone — are needed in different amounts to react to different blockages, Annex explains.
“These are all delicate symphonies,” Dr. Robert Lederman of the NIH’s National Heart, Lung and Blood Institute, said, describing the body’s artery-growing machinery.
So instead of trying to manipulate just one part of the machinery, there’s a new focus on jump-starting the overarching genes that control the process and letting the body finish the job naturally. Among the research:
- At NIH, Lederman began this month the first human study of a genetically engineered substance that acts as a master gene switch. Called a “zinc-finger transcription factor,” it turns on the patient’s own VEGF-controlling gene to spur production of the growth factor’s different forms. In animals, the drug spurred new blood vessels that didn’t leak.
Cummins was the first of 36 PAD patients who will get either the drug, made by California-based Edwards Lifesciences Corp., or dummy injections. While the NIH-financed study mostly tests the injections’ safety, Lederman will use special high-powered MRI scans to hunt any improvement in the leg muscles’ blood flow, key to determining the drug’s promise.
- Massachusetts-based Genzyme Corp. will begin Phase II studies early next year of a different master gene switch.
The body naturally produces this substance, called HIF-1, when tissues run low on oxygen, Annex says. The HIF-1 in turn switches on production of a series of proteins linked to blood vessel formation. Initial testing suggested the injections are safe, with some hints of improved blood flow.
- California-based Valentis Inc. is testing a substance called Deltavasc that essentially forms the scaffolding necessary for angiogenesis. “It works with the theory that everything is there to make a blood vessel; you just need to make the infrastructure,” Annex explained. He expects results from Phase II testing soon.
There’s no way to know which if any will pan out. If nothing else, the new research is focusing important attention on PAD, says NIH’s Lederman. Too many people consider trouble with walking merely a consequence of aging, not disease.
“At my age, if it doesn’t work, it doesn’t work,” said Cummins. “But if this works out, I’m sure hoping it’ll motivate other people to participate in studies such as this, with the outlook that mankind is going to benefit.”
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