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Biotech's bright hope

Scientists are newly optimistic that gene therapy will help fight the most serious diseases.

August 28, 2006|Linda Marsa | Special to The Times

TO the shrill whine of a high-speed drill, neurosurgeon Dr. Paul Larson makes two nickel-sized holes in Shirley Cooper's skull. Guided by a computerized MRI map, he plunges a long, thin needle through one hole and deep into the brain -- and empties the syringe.

A very special payload trickles into her brain: genes that, if all goes well, will help her control the movement of her muscles.

It is a day in late May and Cooper, 60, an artist who lives near Seattle, has come to the UC San Francisco Medical Center to find some relief from the Parkinson's disease that is stealing her identity. Without medication, she has trouble walking and talking, and can't hold a paint brush. And the drugs are wearing off -- as they eventually do for all Parkinson's patients. After that, she probably will deteriorate rapidly.

The experimental treatment Cooper is undergoing is intended to reverse that process. Parkinson's destroys cells in the brain that make dopamine, and the loss of this key brain transmitter triggers the disease's crippling symptoms: tremors in the arms, legs and face, stiff or frozen limbs, and impaired balance and coordination. In the trial she's involved in -- the earliest of clinical tests, designed to assess safety -- scientists have engineered a harmless, stripped-down virus to carry a gene that will boost brain dopamine through the enzyme it encodes: amino acid decarboxylase, or AADC.

When the virus is injected into her brain, they hope the gene will be incorporated into healthy brain cells and steadily produce the enzyme.

Gene therapy is making a comeback after a series of serious setbacks that threatened to permanently derail human tests. In recent years, European scientists have cured more than two dozen patients suffering from three rare, and in some cases lethal, immune disorders.

Spurred by this success, plus the development of new techniques aimed at making the therapy safer and more effective, more than 300 gene therapy trials, including the one for Parkinson's at UC San Francisco, are underway in the U.S. and abroad.

The approaches include what people traditionally think of as gene therapy: inserting functional genes to replace single, faulty ones to treat relatively rare genetic diseases such as muscular dystrophy, cystic fibrosis, sickle cell anemia, beta thalassemia and hemophilia. But, more and more, gene therapy is being studied as a treatment for lethal ills that are not inherited in any clear, simple way -- cancer, hepatitis, AIDS, heart disease -- and which also plague millions.

Today, scientists are injecting genes into people to try to block the formation of deadly cancerous tumors. They're implanting genes that stimulate cell growth in an attempt to regenerate heart muscle cells and grow blood vessels in patients with congestive heart failure; halt disease progression in people with macular degeneration; and slow the death of brain cells in Alzheimer's as well as Parkinson's patients.

Though most of these treatments are still in the early phases of human tests, a gene therapy drug to combat cancer could be available within the year. (See related story).

"There is genuine excitement in the field," says Dr. Ronald Crystal, a gene therapy pioneer and chairman of the department of genetic medicine at Weill Medical College of Cornell University in New York.

"Gene therapy," he predicts, "will evolve into a major therapeutic method."

Progress amid trials

Today's upbeat mood is in stark contrast to the gloom that pervaded the field in the late 1990s. After the rise of genetic engineering in the late '70s, gene therapy had been touted as a magic bullet that would quickly fix an array of debilitating and often fatal inherited ills.

It was nowhere near that simple.

The first human trial was performed in September 1990 at the National Institutes of Health in Bethesda, Md., on a young girl suffering from a rare genetic disease called ADA-SCID, in which the immune system doesn't function properly. Healthy versions of the ADA-SCID gene were successfully added to the girl's blood cells, but she was still taking medication for her condition and doctors couldn't conclude that the gene was providing any benefit.

Even so, it was a breakthrough to show that genes could be added to the body -- and in the wake of that pioneering experiment, more than 450 gene therapy tests were launched, involving 4,000 volunteers.

Not one of those tests cured anyone, according to a 1995 National Institutes of Health report that was commissioned to determine where the field stood scientifically. More damningly, the report concluded that the technology had been tainted by hype, leading to "the mistaken and widespread perception that gene therapy is further developed and more successful than it actually is," the report stated.

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