Direct insertion of skin cells modified to express nerve growth factor into the brains of patients with early Alzheimer’s disease slows the rate of cognitive decline and increases brain metabolic activity, according to study results published online April 24th by Nature Medicine.

Positron emission tomographic (PET) scans demonstrated an increase in the brain’s use of glucose, an indication of increased brain activity, while mental-status tests showed a slowing of the rate of cognitive decline by 36 to 51 percent. In addition, researchers examined the brain tissue of a study participant who died and found robust growth of extensions from dying cholinergic cells near the site of growth factor gene delivery. Cholinergic neuron loss is a cardinal feature of Alzheimer’s disease, a progressive brain disorder affecting memory, learning, attention and other cognitive processes.

“If validated in further clinical trials, this would represent a substantially more effective therapy than current treatments for Alzheimer’s disease,” said Mark Tuszynski, MD, PhD, the study’s principal 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 for Alzheimer’s disease, American physician-scientists took skin cells from eight patients diagnosed with early Alzheimer’s disease. The tissue was modified in the lab to express nerve growth factor. In surgeries that took place in 2001 and 2002 at the John M. and Sally B. Thornton Hospital of the University of California at San Diego, the genetically modified tissue was implanted deep within the brains of the eight patients who had volunteered for the study.

The human clinical trial was undertaken following extensive studies in primates conducted by Tuszynski and colleagues, which showed that grafting growth factor-producing tissue into the brains of aged monkeys restored atrophied brain cells to near-normal size and quantity, and also restored axons connecting the brain cells, essential for communication between cells.

The recent human studies were a Phase I clinical trial, designed to test safety and toxicity. The procedure was initially performed while patients were awake but lightly sedated, and two patients moved as the cells were being injected, resulting in bleeding in the brain. One of these patients died five week later. As a result of the bleeds, the protocol was redesigned to perform the procedure under general anesthesia and all subsequent procedures were performed without complication.

Cognitive outcomes were assessed in the six patients who completed the nerve growth factor delivery procedure safely. The Mini Mental Status Examination (MMSE), which evaluates cognitive function, was administered at screening, the time of treatment and at several intervals after treatment. Over an average post-treatment follow-up period of 22 months, the rate of decline on the MMSE among growth factor-treated patients was reduced by as much as 51 percent. An additional test, called the Alzheimer’s Disease Assessment Scale-Cognitive Subcomponent, or ADAS-Cog, also showed improvements in rates of decline followed the MMSE findings.

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

Based on the positive findings of this Phase I trial, a new Phase I/II study using direct NGF gene delivery to the brain, thereby eliminating the need for grafting cells, is currently underway at Rush University Medical Center in Chicago.