nytimes.com
April 11, 2001
Gene Therapy Is Performed in Bid to Halt Alzheimer's
By SANDRA BLAKESLEE
ix days ago, a woman in the early stages of Alzheimer's disease entered a California hospital, had a small hole drilled through her skull and was injected with millions of her own cells, in what researchers said was the first time gene therapy had been tried on an Alzheimer's patient.
The researchers who announced the experiment yesterday at a news conference held at the University of California at San Diego, where the surgery took place, said it was also the first time that doctors had tried to prevent progressive cell loss in a neurodegenerative disease.
The 60-year-old patient, who asked to remain anonymous, was discharged from the hospital last Saturday and is recovering well at home, said Dr. Mark Tuszynski, a neurologist at the university who led the research.
"We hope to learn within the next three months if the procedure is working," Dr. Tuszynski said in a telephone interview. "But this is just one patient. It may take years before we know if it works in a large number of people."
Dr. William Mobley, the chairman of the neurology department at Stanford University, who is familiar with the research, called the procedure "a very important first step" toward finding a novel way to treat Alzheimer's disease.
"The work is being done very carefully," Dr. Mobley said. "Their logic is very good."
That logic is based on 20 years of exploring the changes that accompany normal aging of the human brain and the disease processes that lead to dementias like Alzheimer's disease, Dr. Tuszynski said. Both conditions share certain biological mechanisms. For example, higher brain regions where language, memory and other cognitive functions reside are nourished by a chemical substance made in a small clump of cells, the nucleus basalis, found deep in the brain just under each frontal lobe. About the size of a human thumb nail, the nucleus basalis makes a substance, acetylcholine, which is sent to target cells all over the brain.
Acetylcholine modulates the excitability of distant neurons, increasing or decreasing their electrical activity depending on the amount of the chemical supplied by the nucleus basalis.
When a cell in a distant area gets particularly excited and needs more acetylcholine, it sends a signal, called nerve growth factor, back to the nucleus basalis telling it to make more.
In Alzheimer's disease, some still mysterious process kills cells throughout higher brain regions and the nucleus basalis does not get the nerve growth factor it needs to prod it into making more acetylcholine. Without acetylcholine, higher brain areas that control things like memory, attention, personality and the ability to navigate through space can be severely impaired.
The gene therapy experiments are designed to fix this state of affairs by putting a source of nerve growth factor back into the nucleus basalis. First, researchers took skin cells from the Alzheimer's patient and inserted the gene that makes nerve growth factor. By adding substances that promote gene expression, they turned her skin cells into tiny nerve growth factor pumps.
Then Dr. Hoi Sang U, the neurosurgeon on the team, injected two and one-half million cells that produce nerve growth factor next to the patient's right nucleus basalis. The new cells are expected to produce enough nerve growth factor to bring atrophied cells back to life.
In aged monkeys, the same procedure not only stopped cells from dying, it also revived them from their atrophied state, Dr. U said. "They got plump. And their many target cells made new connections."
Whether the therapy will restore memory loss in Alzheimer's patients is not known, Dr. Tuszynski said. The hope is that it will at least slow the disease process. The patient, a former teacher from Oregon, will be tested in coming weeks and months to see if her right hemisphere regains any function or if it maintains function compared with the untreated side of her brain.
Dr. Tuszynski said a second patient would receive genetically engineered cells in three months, again on one side of the brain. If no harm is detected, six more patients will receive the engineered cells in both sides of the brain. |
