Genetic Therapy Effective for Alzheimer's

Positron emission tomography (PET) scans and cognitive testing have demonstrated that patients with Alzheimer's disease (AD) who were treated with genetically engineered tissue inserted directly into their brains show a decrease in the rate of cognitive decline and increased metabolic activity in the brain, according to a new study.

The PET scans showed an increase in the brain's uptake of glucose, a sign of increased brain activity, whereas mental status testing demonstrated a decrease in the patients' rate of cognitive decline, which was reduced by 36-51%. Additionally, the scientists, from the University of California, San Diego (UCSD) School of Medicine (USA), evaluated the brain tissue of a study participant who had died and discovered a vigorous growth of extensions from the dying cholinergic cells near the site of growth factor gene delivery. Cholinergic neuron loss is a major characteristic of AD. The study was published in the April 24, 2005, issue of the journal Nature.

"If validated in further clinical trials, this would represent a substantially more effective therapy than current treatments for Alzheimer's disease,” said Mark Tuszynski, M.D., Ph.D., UCSD professor of neurosciences, and the study's lead investigator. "This would also represent the first therapy for a human neurological disease that acts by preventing cell death.”

In this first-ever gene therapy study for AD, UCSD researchers took skin cells from eight patients with AD. The tissue was modified in the laboratory to express nerve growth factor (NGF), a naturally occurring protein that blocks cell death and activates cell function. Between 2001 and 2002, the genetically engineered tissue was implanted deep within the brains of eight patients who had volunteered for the study.

In earlier studies with primates, the grafting NGF-producing tissue restored atrophied brain cells to nearly normal quantity and size, and also restored axons connecting the brain cells, which are essential for communication between cells. This human phase I clinical trial was designed to assess toxicity and safety. The procedures were first performed while patients were awake but slightly sedated, and two patients moved as the cells were being injected. Two patients died five weeks later. As a result of the hemorrhaging, the protocol was reworked to perform the procedure under general anesthesia, and all the following procedures were performed without complications.

Cognitive outcomes were evaluated in the six patients who completed the NGF delivery procedure safely. The Mini Mental Status Examination (MMSE), which assesses cognitive function, was given at testing, the time of treatment, and at several intervals after treatment. Over a median post-treatment follow-up period of 22 months, the rate of decline on the MMSE among NGF-treated patients was decreased by as much as 51%. Another test, called the Alzheimer's disease assessment scale-cognitive subcomponent (ADAS-Cog), also demonstrated improvements in rates of decline followed the MMSE results.

Post-operative PET scans in four individuals demonstrated considerable increases in the brain's absorption of a radioisotope called 18-fluorodeoxyglucose, an indicator of increased metabolic activity in the brain. The investigators observed that the increase was noted in most cortical areas that receive cholinergic input from forebrain nerve cells called the nucleus basalis, and in the cerebellum, a structure associated with cortical plasticity.




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