Alzheimer's Gene Therapy Slows Mental Decline

Not a Likely Cure, Say Researchers Testing Gene Therapy

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April 25, 2005 -- A new approach to Alzheimer's disease uses gene therapy to slow down the disease.

When tried for the first time in humans, the mental decline from Alzheimer's slowed. Metabolic brain activity also increased, according to the report in Nature Medicine's online edition.

The study was very small, with only eight patients. More studies are needed, say the researchers, who included neurosciences professor Mark Tuszynski, MD, PhD, of the University of California, San Diego.

The strategy didn't cure Alzheimer's disease and isn't likely to do so, they caution. But if confirmed, it might be "a useful therapy" that could surpass current Alzheimer's treatments.

First Human Tests

The technique is the first gene therapy for Alzheimer's disease, according to a news release. Previously, it was tested on nonhuman primates.

The participants -- five women and three men with Alzheimer's disease -- were followed for nearly two years, on average.

At the study's start, participants were about 67 years old and were in the early stages of the disease. It had been about 4.5 years since their Alzheimer's symptoms were first noticed and about two years since the probable diagnosis was made (Alzheimer's is definitively diagnosed when the brain is examined after death).

Each volunteer got mental tests and brain imaging scans before the procedure and at regular intervals during the two-year follow-up. That gave researchers a before-and-after look at participants' progress.

Using Skin Cells to Help the Brain

Researchers took skin cells called fibroblasts from each patient. In a lab, they genetically modified the cells to make and secrete nerve growth factor (NGF), a naturally occurring protein that prevents nerve cell death and stimulates cell function.

The modified cells were then inserted into each person's brain in a region affected by the disease.

At first, participants were sedated but awake while the cells were injected. Two patients moved during the procedure, causing bleeding in the brain. One died five weeks later. The other patient had temporary weakness on one side of the body and a worsening of dementia-related speech and language problems.

Later patients got general anesthesia during the procedure.


The treatment slowed but didn't cure or completely stop Alzheimer's disease progression.

The follow-up focused on the six patients who had no problems during the procedure. Their scores on mental tests showed that mental decline was about half as slow (51%) during the 22 months or so after the procedure than before the operation.

Brain imaging scans also showed significant increases in metabolic activity in the brain. That's the opposite of what usually happens in Alzheimer's disease, say the researchers.

The researchers received permission to do an autopsy on the participant who died. They saw "robust growth responses to NGF" in that patient's brain.

No side effects due to NGF gene therapy were reported during the study.

Key System Targeted

Brain cells called cholinergic neurons -- nerve cells that use the neurotransmitter acetylcholine to transmit their signals -- were the experiment's target. Those cells typically suffer in Alzheimer's disease, but so do other brain systems, say the researchers.

"NGF is unlikely to 'cure' the disease," write the researchers.

The disease's wide-ranging brain devastation probably wouldn't be completely stopped just by focusing on cholinergic neurons, they say.

However, they note that mental decline slowed more than what's been seen with current therapies.

"Currently approved medications for Alzheimer's disease have an estimated impact on these cognitive measures of 5% and are not known to affect decline over long periods," write researchers.

About Alzheimer's Disease

An estimated 4.5 million people in the U.S. have Alzheimer's disease, says the Alzheimer's Association.

A progressive brain disease, Alzheimer's impairs parts of the brain related to memory, intelligence, language, behavior, and judgment.

Alzheimer's becomes more common with age and is the most common form of mental decline in older adults, but it's not a natural part of aging. Alzheimer's affects one in 10 people older than 65 and nearly half of those older than 85, says the Alzheimer's Association.

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SOURCES: Tuszynski, M. Nature Medicine, April 24, 2005; online edition. News release, University of California, San Diego. Alzheimer's Association, "Statistics About Alzheimer's Disease." WebMD Medical Reference from Healthwise: "Alzheimer's Disease: Topic Overview."
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