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Staving Off Alzheimer's Disease

Treatment: Doctors are awaiting the results of their first attempt at gene therapy for a patient in early stages of the illness.


For the first time, doctors have attempted gene therapy in an Alzheimer's patient, a former Oregon schoolteacher in the early stages of the disease.

But it may take months before they know if the procedure, performed in early April, had any effect.

"This will not cure the disease, but the hope is it can significantly improve quality of life for a certain time period," possibly years, said Dr. Mark Tuszynski, a neurologist leading the research at UC San Diego.

The researchers are hoping that cells taken from the patient's body, altered and implanted in her brain, will help stave off mental deterioration.

This new direction in Alzheimer's therapy could hold hope for some of the 4 million Americans with the progressive neurological illness, for which there is no cure and only limited medications.

Tuszynski and his colleagues are betting that the cells implanted in the brain will become, in essence, little chemical factories churning out nerve growth factor that might keep some brain cells from dying. Just how much growth factor they'll produce and for how long remain to be seen.

"I think that if it works, the patient doesn't reject it and there are no complications . . . it's a very important step in developing new treatments for Alzheimer's," said Dr. Zaven Khachaturian, scientific and medical advisor to the Alzheimer's Assn.

Tuszynski said similar gene therapy is expected to be tried in the next few years against Parkinson's disease and possibly other degenerative brain disorders, such as Lou Gehrig's disease and Huntington's disease.

Gene therapy, first attempted in 1990, remains a promising area of disease treatment, even though the hundreds of clinical trials so far haven't lived up to the initial hype of producing cures. Doctors still hope to use it to treat a broad range of illnesses, from inherited ailments to diabetes, cancer and heart disease.

In the Oregon woman's case, surgeons drilled a nickel-sized hole in her skull and made five injections into a region about the size of a thumbnail. With the patient sedated but conscious, they injected just two drops of fluid containing 2 1/2 million engineered cells.

The patient has been recovering well with no complications. She is due to return for tests this week and will be monitored for the next three months. If all goes well, seven others will undergo the same surgery.

The 11 1/2-hour operation used technology that previously had been successful in protecting the brain cells of mice and monkeys. In those studies, researchers detected the effects within weeks to months.

"However, to know overall whether nerve growth factor is beneficial for the treatment of Alzheimer's disease will take several years," Tuszynski said.

The new procedure was designed to make cells harvested from the woman's own skin deliver more nerve growth factor where it's needed. The growth factor has been shown to prevent the death of those brain cells that use acetylcholine. In Alzheimer's disease, these cells are damaged, contributing to a decline in memory and intellect.

Up to now, pharmaceutical researchers have been looking for ways to keep larger amounts of acetylcholine bathing brain cells. That's the concept behind the current group of Alzheimer's drugs such as Cognex, Aricept, Exelon and the newly approved Reminyl, all of which keep acetylcholine from breaking down and thus keep damaged cells working longer.

But the researchers who devised the gene therapy knew from experience that nerve growth factor can prevent the death of cholinergic cells. They also knew from Swedish studies that pumping nerve growth factor directly into the brain caused unpleasant side effects, including pain, weight loss and unwanted cell growth around the brain and spinal cord.

What they sought was a way to get nerve growth factor right where it could go to work, without exposing other brain cells to it.

They began taking cells culled through tissue biopsies and genetically engineering them in a test tube so they'd make the gene that instructs cells to produce nerve growth factor. Then, they implanted those engineered cells in animals' brains in the hopes they'd act as pumps for the growth factor--and continue to pump the chemical for extended periods. It worked.

In aging monkeys, shrunken brain cells became rejuvenated, and important connections to other parts of the brain were restored too. And in 200 monkey trials, there were no unwanted tumors or other dangerous effects.

In 1999, the FDA gave the go-ahead to human trials.

Although Alzheimer's disease is most destructive during its middle stages, researchers designed the Phase I trial, meant to establish the safety of using the method, for early-stage patients who were otherwise healthy. In the early stage, Alzheimer's patients have some short-term memory loss but have nearly normal ability to reason and understand--abilities researchers deemed important to obtaining informed consent.

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