First-ever gene therapy for treating Alzheimer's
San Diego researcher tells of positive results with a few patients in report to S.F. meeting

Carl T. Hall, Chronicle Science Writer

Wednesday, April 28, 2004

Despite some early disasters, a novel gene-therapy treatment for Alzheimer's disease has produced encouraging results in the first half-dozen patients, scientists reported Tuesday.

After years of animal studies, researchers led by Dr. Mark Tuszynski, a neuroscientist and neurologist at UC San Diego, began the first human safety trial of the new approach in April 2001. Tuszynski summarized the results during the annual meeting of the American Academy of Neurology, which is under way this week in San Francisco.

The study has drawn attention as the first attempt to use gene therapy to treat an incurable neurodegenerative disorder. Alzheimer's disease currently affects about 4 million people in the United States, and that number is growing as the population ages.

Gene therapy has been touted as a way of curing some of the most intractable diseases known, typically by injecting a benign virus or other "vector" to deliver therapeutic genes inside a patient's own cells. But the first studies were fraught with safety problems that cooled some of the early enthusiasm.

In the Alzheimer's study, the idea was to increase the output of a natural protective substance called nerve growth factor in a thumbnail-size region of the brain, from which a critical type of nerve cell sends projections throughout the cortex. Those cells have been shown to die off in Alzheimer's cases, contributing to the profound memory loss and confusion that are hallmarks of the disease.

The scientists took skin cells from each patient, modified the cells genetically so they would secrete the nerve growth factor, then injected the cells into holes drilled into the patients' heads. Eight patients were enrolled in the study, which was designed only to establish whether the elaborate method could be safely tried in humans.

Two patients suffered brain hemorrhages from injuries incurred during the implantation surgery, Tuszynski said, leading to the death of one person five weeks after the procedure. The other patient recovered.

Patients initially were kept awake during the surgery, as is often the case in neurosurgery. The accidents happened when the patients moved their heads at a critical time, Tuszynski said.

That forced a change in procedures so that the other study participants were put under anesthesia and immobilized, which prevented more incidents.

The trial produced no evidence of any safety problems involving the altered cells or the nerve growth factor, which can produce powerful toxic effects if overabundant in the wrong brain regions.

Nor did the injection cure anyone's disease. On standard neurological tests, the six patients showed a marked slowdown in the rate of cognitive decline typical for an Alzheimer's patient. Also, an autopsy of the patient who died showed the injected cells functioned as hoped -- Tuszynski likened them Tuesday to "biological pumps" implanted in the brain.

"This is the kind of results you like to see in a Phase 1 safety trial," he said.

But the apparent benefits could just be the result of chance -- or the wishful thinking of the researchers.

The experiment included none of the standard controls researchers must use in trials designed to prove that a treatment truly works. Two of the scientists, including Tuszynski, are co-founders of a San Diego biotechnology firm, Ceregene Inc., which holds a commercial stake in the enterprise.

The planned next step will be another six-month safety trial of a modified approach, in which the critical genes are to be injected directly into the brains of patients, eliminating the need for using the doctored skin cells. Assuming that study reveals no new safety concerns, the first true test of efficacy could begin in about 30 patients, including sham surgeries and other experimental controls. Those patients are expected to be tracked for about two years.

E-mail Carl Hall at chall@sfchronicle.com.