Schizophrenia Daily News Blog

Gene Therapy for the Brain

Gene Therapy Slows Alzheimer's Cognitive Decline

In a development that highlights the potential to mitigate brain diseases (such as Schizophrenia) via gene therapy, The University of California, San Diego (UCSD) announced today that Alzheimer's Cognitive Decline Slowed In Gene Therapy Patients.

PET scans and cognitive tests have suggested that Alzheimer's disease patients with genetically modified tissue inserted directly into their brains show a reduction in the rate of cognitive decline and increased metabolic activity in the brain, according to a study published in the April 24, 2005 online issue of the journal Nature Medicine by researchers at the University of California, San Diego (UCSD) School of Medicine.

Above: Averaged FDG PET scan images in four subjects treated with NGF, overlaid on standardized MRI templates. Representative axial sections, with 6-8 months between first and second scan, showing widespread interval increases in brain metabolism. Flame scale indicates FDG use /100g tissue/min; red color indicates more FDG use than blue. (Image courtesy of University Of California - San Diego)

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 patients' rate of cognitive decline was reduced by 36 to 51 percent. In addition, researchers examined the brain tissue of a study participant who had died and found robust growth of extensions from the 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, M.D., Ph.D., UCSD professor of neurosciences, neurologist with the VA San Diego Healthcare System, and 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, UCSD 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 (NGF), a naturally occurring protein that prevents cell death and stimulates cell function. In surgeries that took place in 2001 and 2002 at UCSD's John M. and Sally B. Thornton Hospital, 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 NGF-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.

Cognitive outcomes were assessed in the six patients who completed the NGF 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 NGF-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.

In addition to Tuszynski, authors of the paper in Nature Medicine, were Leon Thal, M.D., UCSD chair of neurosciences, director of the UCSD Shiley-Marcos Alzheimer's Disease Research Center (ADRC), and a neurologist with the VA San Diego Healthcare System; Mary Margaret Pay., and others.

The study was supported by the Institute for the Study of Aging and the Shiley Family Foundation.