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DNA Instead of Drugs Doctors Search for Cures for Heart Disease, Cancer and Other Illnesses in the Human Genome

Posted on: Monday, 28 March 2005, 21:00 CST

As his cardiologist snaked a catheter up inside his heart, Joseph DePretto figured he had nothing to lose.

Doctors had already performed two bypass surgeries and a balloon angioplasty, implanted a pacemaker/defibrillator and prescribed a host of drugs.

But DePretto's arteries stubbornly refused to remain open, and he suffered severe fatigue and shortness of breath as a result. So on this day, DePretto, 64, of Bensenville, pinned his hopes on an experimental treatment that aims to trigger the heart to heal itself.

"You're gambling, but I think it's worth the chance," DePretto said. "I don't want to go in for another bypass, which I think at my age would be too risky."

The treatment involves injecting the heart with pieces of DNA that trigger new blood vessels to grow, increasing blood flow and oxygen to the heart. The procedure is still experimental, and doctors aren't sure whether patients like DePretto will see any improvement in symptoms.

Yet, cardiologists nationwide are eagerly following the trial of the "growth factor" gene called VEGF-2. Gene therapy is cutting edge research in heart disease, partly because doctors have run out of other cures. Half the 500,000 bypasses performed each year eventually fail because the arteries plug up again with fatty plaque after surgery.

"In cardiology, we're kind of running up against a wall," said Dr. Louis McKeever of Midwest Heart Foundation, who is conducting the study at Elmhurst Memorial Hospital. "It's the next thing that we can offer. Everything we have up to now doesn't treat 100 percent of the patients."

So far, few cures have materialized from gene therapy. Yet researchers in difficult disorders like cancer, cystic fibrosis, hemophilia, sickle cell and heart disease are hopeful that as the VEGF-2 trial and others continue, they'll succeed in finding a way to harness the human genome to cure what ails us.

Healing genes

The theory is simple enough. Use a safe virus to carry copies of a gene into the cells of people with genetic diseases, whose own versions of the gene are defective. The new gene triggers the body's mechanisms to protect health and heal disease.

So far, most studies have been approved for only the sickest patients, and few have progressed to the most advanced stages of research, in which scientists test a therapy in large numbers of patients and compare it to conventional treatments.

"I think there are a lot of therapies that are really close, but we're not quite there yet," said Dr. Mark Kay, a professor of pediatrics and genetics at the Stanford School of Medicine and president-elect of the American Society of Gene Therapy.

The first gene therapy product to be approved for sale anywhere in the world, a virus that carries a cancer-fighting gene, came on the market in China in 2003.

In the United States, despite great expectations in the early days of gene therapy research, an approved therapy is still years away. The majority of research has shifted to common diseases like heart disease and cancer, which have more complex causes than single- gene diseases. The largest share of gene therapy studies - roughly 65 percent - are testing treatments for cancer.

One promising line of research involves using radiation or chemotherapy to "turn on" a gene carried into cancer tumors by a virus.

Dr. Ralph Weichselbaum, professor and chairman of radiation oncology at the University of Chicago, developed a technique using tumor necrosis factor, a potent substance that kills cancer cells. Because TNF is toxic when given systemically, researchers altered it so it could be "turned on" by radiation after it was injected directly into a tumor.

Small, initial studies showed promising results, and the technique is now being tested in a larger trial.

"It's intriguing, but it's very preliminary," Weichselbaum said. "It could change the way we do radiotherapy if it works."

Gene therapy research is also focusing on cystic fibrosis, a disorder that results in chronic respiratory infections. Scientists have figured out how to transfer a normal gene into the airways of patients with cystic fibrosis, and patients in Phase 2 trials showed a temporary improvement in symptoms.

Even this promising treatment, however, does not represent a true "cure." Patients would have to treat their illness as a chronic disease like diabetes or asthma.

"If you could go in and put a good copy of the gene into every cell of the body, it would indeed be a cure," said Rex Chisholm, director of the Center for Genetic Medicine at Northwestern University. "But it's very hard to do that. So what they're doing is putting it in the cells in the airway, where it is the most acute problem."

Gene therapy's most definitive success thus far has been in treating a disorder related to "bubble boy" syndrome, which destroys patients' immune systems. Fourteen boys in France were cured of X- linked severe combined immunodeficiency, or X-SCID, a potentially fatal disorder, and were able to live normal lives.

Recently, however, two of the children developed leukemia. The virus used to carry the therapeutic genes found the one gene that triggers cancer.

Genetic hurdles

The X-SCID case illustrates some of the challenges of gene therapy. Even when scientists find a way to get DNA into cells - and it works - there is still the chance it will behave in unexpected ways.

In 1999, the controversial death of 18-year-old Jesse Gelsinger during a gene therapy trial at the University of Pennsylvania launched a massive investigation into the field, slowing research and increasing scrutiny. The U.S. Justice Department announced a settlement earlier this month with the scientists who ran the trial.

Today many gene therapy trials are gearing up - waiting only FDA approval - to search for cures for cancer, hemophilia, congenital blindness and other difficult disorders.

"I think gene therapy really will play a major role in medical treatment in the future," Kay said. "It has great potential, but it's just going to take time to get through some of the technical hurdles."

The first obstacle is finding the right genes. But an even bigger problem is often getting them to the right place in the human body.

Scientists have learned how to harness a virus and make it carry the gene, a sort of molecular Trojan horse. Viruses are well-suited to the work because they are designed to invade cells, often very specific cells in the body.

But they can also cause unforeseen side effects, and if our immune system recognizes them as foreign they may be destroyed before achieving any therapeutic effect.

The VEGF trial avoids this problem by skipping the virus entirely. In the current study, cardiologists are injecting "naked" DNA directly into areas of the heart where they hope to grow new blood vessels.

Because it has no viral vector to replicate, the DNA itself eventually disappears. By then, hopefully, it has already triggered the creation of proteins that stimulate new blood vessels to grow.

Doctors have reasons for optimism. Other trials using the growth factor genes have shown success. In one study, patients with poor circulation avoided leg amputation after gene therapy helped them grow new blood vessels.

In the heart itself, doctors have tried using various genes that code for different growth factors. They've experimented with delivery methods, too, using viruses or injecting the DNA into arteries instead of muscle tissue.

Dripping genes into arteries didn't work, perhaps because the genes didn't stay in place long enough to have a therapeutic effect. Doctors are more hopeful about injecting DNA directly into the heart.

"All the therapy that injects the therapy right into the heart muscle has been encouraging," said Dr. Todd Rosengart, head of cardiothoracic surgery at Evanston Northwestern Health Care. "The field is going to be very dependent on the outcome of these pivotal trials."

Besides Midwest Heart Foundation, the VEGF-2 trial is also being conducted at Rush University and numerous sites nationwide. Researchers expect it will take at least three months before patients notice any effect.

Participants are limited to those with severe angina who have failed to get better with conventional treatments. A quarter of patients will receive a placebo, and 75 percent will receive either a small, medium or large dose of the DNA.

Hypothetically, the DNA could stimulate the growth of new blood vessels elsewhere in the body, including tumors. Patients must be free of cancer and diabetic retinopothy, a disorder characterized by the proliferation of blood vessels in the retina.

If it works, gene therapy could give doctors another tool in their battle against heart disease.

"The gene therapy trials are terribly exciting and possibly of great importance," said Dr. Nirat Beohar, a cardiologist at Northwestern Memorial Hospital who is not involved in the study. "Even though we've made a lot of progress with angioplasty and bypass, there is a good percentage of the population whose arteries are so blocked up you can't do it. The challenge is to help these people."

Source: Daily Herald; Arlington Heights, Ill.

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