IT’S THE biggest killer in the developed world. Even if you are spared, chances are that cardiovascular disease will claim a third of your friends and loved ones. Before they die, many will endure major surgery, years of dependence on drugs and the uncertainty of living with a terminal condition. The incentive to find a cure is huge. What if there’s a simple treatment that could do away with open-heart surgery, perhaps even prevent heart attacks altogether?
Sounds too good to be true? Well, there is a catch. Patients would be injected with proteins or the DNA that codes for them. But these “growth factors” are the same proteins that cancer cells pump out to trick the body into sprouting new capillaries to feed the tumour. Cancer researchers are understandably keen to turn off this angiogenesis. A few pioneers, though, realised that being able to grow blood vessels at will would be a formidable weapon against cardiovascular disease—even if it means injecting patients with bits of DNA from tumours.
The stakes are enormously high. Three hundred million patients in the developed world alone stand to benefit from a therapy that would stimulate the growth of new blood vessels to replace diseased or blocked ones. After 10 years of work and some hefty business finance, researchers are starting to believe they’re onto something big. One of the most outspoken advocates, William Li of Harvard Medical School and the Angiogenesis Foundation in Cambridge, Massachusetts, puts it like this: “Angiogenesis therapies promise to be to 21st century medicine what antibiotics were in the 20th century.”
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The body’s vast cardiovascular system is its largest tissue; strung end to end, the arteries, capillaries and veins in your body could stretch twice around the globe. Normally, blood flows without a hitch and you scarcely give this vital network a second thought. But with advancing age and a fatty diet, atherosclerotic plaques can begin to form on the inner walls of arteries. As they grow, blood flow around them becomes more turbulent and slows until eventually a plaque may block the tubes entirely. If this happens in the coronary arteries that feed the heart, it becomes sluggish, blood pressure drops and other organs begin to suffer. Welcome to the grim world of coronary disease.
Existing therapies are daunting: cut-and-graft surgery to reroute the arteries around the heart, or balloon-like stents to prop open blocked vessels. Despite huge advances in these treatments, they’re still unsuitable for hundreds of thousands of patients. Besides, they are only stop-gap measures. One in five bypass patients will need new surgery within a year, and up to a third of patients die within five years. True, improved drug therapy means you can live for years with heart disease, but there is no cure. Which is why building brand new vessels to replace the diseased ones is such an attractive option.
Angiogenesis isn’t unique to tumours. All healthy people produce proteins that promote and inhibit the growth of blood vessels. They play key roles in normal fetal development and, although adults tend not to grow new blood vessels, there are exceptions. In women of reproductive age, for example, the lining of the uterus is repaired every month. A certain amount of angiogenesis also happens naturally around damaged tissue after a heart attack, stroke or traumatic injury.
But it’s not enough for a full recovery and that’s where tumour cells come in. They are better at promoting angiogenesis than healthy adult cells. Understanding how they do this could help treat cardiovascular disease as well as being a vital key to curing cancer.
So far, researchers have found 30 angiogenesis inhibitors in the human body and cancer drugs based on some of these should soon start to appear. Nineteen growth factors have also emerged from the flurry of activity and they could alleviate other diseases. “Angiogenesis is already benefiting tens of thousands of patients,” says Li. Genetically engineered platelet-derived growth factor (PDGF)—marketed since 1998 as Regranex gel—has revolutionised the treatment of chronic wounds such as diabetic foot ulcers which would have otherwise meant amputation. Angiogenesis works for wounds, says Li, so why not for other parts of the body?
Two of a bunch of five growth factors now in the melting pot look like winners: vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). They have put heart disease and peripheral artery disease next in line for angiogenesis treatments, and they may also help reverse the brain damage caused by strokes (see “Stroke of genius?”)
In animal studies treatment with FGF and VEGF triggers angiogenesis after a heart attack and also in animals with atherosclerotic arteries in their hind legs. Now dozens of labs around the world are trying the treatments in human patients. In Germany, for example, heart surgeon Bernd Schumacher and his team at Ulm University Hospital injected FGF directly into the heart muscle of 40 patients who had just had coronary bypass surgery. The protein triggered a flurry of capillary growth. Three years later, in 2000, these patients had a 13.5 per cent increase in blood pumping out of the left side of their heart—almost twice the improvement in people who had only had the surgery.
Another pioneering study gives hope to the millions suffering from chronic peripheral arterial disease. A leading killer in the developed world, it normally affects people’s legs, is excruciatingly painful and severely limits how far you can walk. Jeffrey Isner from Tufts University injected VEGF genes from human pituitary tumours into the legs of 20 patients.
Using genes from cancer cells sounds like a huge risk, and even Isner had doubts. “Hoping that that kind of shot was going to save somebody’s leg was almost crazy,” he told reporters shortly before his death last October. “I thought… this is the closest thing to voodoo that I’ve ever been involved with.” But his results in 2000 were impressive: circulation improved in three quarters of his patients. A year after treatment, five still had improved blood pressure in their legs and increased mobility.
Not every growth factor study has produced encouraging results. In two separate trials sponsored by US biotechnology companies Genentech and Chiron, for example, growth factor injections were no more effective than placebos in patients with inoperable heart disease and peripheral arterial disease. Li argues that these studies didn’t run long enough to reveal the benefits of growth factor injections and failed to recognise that patients with the most severe symptoms at the start of the trial responded the best.
But some researchers aren’t sure the treatment will ever work. “It’s an unproven therapy,” is how Kirk Hammond from the University of California at San Diego puts it.
Then there is the question of safety. Even if growth factors can help cure cardiovascular disease, might they also trigger growth in tiny tumours that have lain dormant for lack of a blood supply? Experiments with mice reveal that injecting high concentrations of VEGF directly into the heart can lead to tumour growth.
But human patients would never get such high doses, says Stephen Epstein, director of the Cardiovascular Research Institute at Washington Hospital Center in Washington DC. No tumours have appeared in the hundreds of volunteers in the various clinical trials, he says, but nobody knows whether patients’ cancer risk will increase in the long run. “These are very potent molecules with many effects, so we have to be cautious,” he says.
The accumulated knowledge of cancer researchers suggests cautious optimism, though. “It takes very high levels of growth factor to speed up tumour growth,” says Judah Folkman from Harvard University, who discovered the role these proteins play in cancer. “It turns out that VEGF has very fast clearance [from the blood system],” he adds. So cancers are unlikely to be exposed to the sustained, high levels of growth factor they need for capillary growth, even if the proteins find their way into the general circulation.
The challenge now for therapeutic angiogenesis researchers is to find ways to target sustained doses of growth factor at specific diseased tissues. One promising approach involves implanting polymer beads that slowly release the proteins. Alternatively, researchers can inject genes for growth factors into target tissues, as Isner did.
This latter technique was declared safe just last month, by Cindy Grines from the William Beaumont Hospital in Royal Oak, Michigan, and her team. They used an inactive virus to carry a human FGF gene into the hearts of 60 people with angina. On average, 87 per cent of the viral material stayed put, and the low levels of FGF protein that did make it into the patients’ general circulation seemed to have no ill effects. “We’re not seeing any indication of [tumour growth] being a problem,” says Grines. The patients’ fitness improved significantly, but only larger studies will determine whether the treatment works or not. These are under way at 100 centres in the US.
Even if researchers can crack the problem of delivering a sustained and localised supply of growth factor, there’s another big challenge. So far, they’ve only managed to grow capillaries. What they really need are fully fledged arteries to keep the new capillary networks well supplied with blood and, one day, allow doctors to coax the heart into performing its own bypass operation. But artery walls are more sophisticated than capillaries—they contain more layers of smooth muscle and the arrangement of endothelial cell linings is more complex.
Complete toolbox
To grow arteries, doctors would need to give patients a range of growth factors simultaneously, and they’ve just taken a first step. Last November, a team led by Thomas Richardson and Martin Peters at the University of Michigan, Ann Arbor, reported capillary growth in rats and mice injected with tiny time-release polymer beads containing two growth factors (Nature Biotechnology, vol 19, p 1029). But we are still far from understanding the natural process of artery formation. “We don’t know a tenth of the genes involved in angiogenesis,” says Epstein. “Even if we did, there’s no practical way that we could give a patient all of them.”
Perhaps we won’t have to. Epstein is using endothelial stem cells found in adult bone marrow—the precursors of cells that form blood vessel linings—to try to stimulate angiogenesis in people with heart disease. The cells contain a complete set of activated growth factor genes and Epstein has taken them from his patients’ marrow and then injected them back into their heart muscles. “It makes sense to try using the whole toolbox instead of just a hammer,” he says.
The results of this particular study aren’t out yet, but doctors may soon be treating cardiovascular disease with therapeutic angiogenesis. “We’re still a few years away from routine clinical treatment,” Epstein says, “but I think we’ll get there.” Grines’s estimate is five to 10 years.
Li is even more upbeat. Controlling blood vessel growth won’t just revolutionise the treatment of heart disease and cancer, he believes. It will give doctors a handle on all sorts of problems from healing wounds and fractures, minimising brain damage in people with neurodegenerative diseases and strokes, and combating childhood growth disorders, to treating infertility, obesity and even baldness. “No aspect of medicine will be untouched,” says Li.
Stroke of genius?
THE brain reacts to a stroke by desperately trying to grow new blood vessels. Cells at the peripheries of the damaged area secrete vascular endothelial growth factor (VEGF), which stimulates capillary growth and increases blood vessel permeability—breaking down the blood-brain barrier long enough to allow housekeeping cells to cart off dead brain tissue. Surviving neurons become unusually lithe and adaptable as they try to restore damaged connections. But even the brain’s best efforts are often too slow to avoid permanent brain damage.
Turning up the volume on the recovering brain’s intricate biomolecular orchestra could help. By giving extra VEGF to rats that had suffered a stroke, Michael Chopp of the Henry Ford Hospital in Detroit, Michigan, dramatically increased the density of blood vessels in the damaged areas. And the rats given VEGF recovered more completely, getting back more motor and sensory function than untreated animals. Chopp believes that therapeutic angiogenesis has “great potential” for treating people who have suffered a stroke.
But there is a snag. Injecting VEGF into the brains of rats made their blood vessels leaky. That means there’s a high risk of fluid build-up, otherwise known as cerebral oedema, according to David Greenberg of the Buck Institute of Age Research in Novato, California. “Combined treatment with other angiogenic growth factors might get around this problem,” he says.
Greenberg believes such treatment could help people recovering from strokes, but he suspects the best results are likely to come in prevention—growing new capillaries in patients who have had a stroke to minimise the risk of another one.
- Further reading: “Myocardial gene therapy” by Jeffrey Isner, Nature, vol 415, p 234 (2002) Therapeutic angiogenesis special issue, Cardiovascular Research, vol 49, issue 3 (2001)