Altered Cell Seen as Future Therapy for Memory Loss
Researchers have for the first time implanted genetically engineered skin cells into the brains of laboratory animals to correct a neurological defect.
A UC San Diego research team, headed by neuroscientist Fred H. Gage, reports in Friday’s Science magazine that the engineered cells secrete a hormone called nerve growth factor, which sustains brain cells that would otherwise die because they have been deprived of the hormone from natural sources. The animals’ condition mimics some aspects of Alzheimer’s disease, although the human disease is much more complex.
Although the research is still in its formative stages, scientists believe that it has great potential for use in humans because the same genetic engineering technique could be used to produce cells that would serve as a therapy for Parkinson’s disease, which is now being treated on an experimental basis with adrenal tissues and with fetal brain tissues.
Ethical Issues
The use of engineered cells, which could be obtained from the patient’s own skin, would eliminate the ethical issues associated with the use of fetal cells obtained during abortions and might lead to better results in the operation, experts said.
“The theoretical advantages of this approach are so tremendous that, within a decade, it will be the only way to go,” said neurologist Don Marshall Gash of the University of Rochester School of Medicine in New York.
“The concept is a good one and a viable one, and requires a lot of attention, and may very well get us away from the need to find fresh fetal neurons,” added neurologist Donald Stein of Rutgers University in Newark, N.J.
Gage and his team studied a group of brain cells called cholinergic neurons, which are important in certain memory processes. The cholinergic neurons are connected to the brain’s hippocampus, which secretes nerve growth factor, through a pathway called the fimbria-fornix.
Loss of Memory
If the fimbria-fornix of a rat is surgically severed, the cholinergic neurons lose their supply of nerve growth factor and die off within two weeks. As the cells die, the rat loses some of its spatial memory function. Gage tests this function by training the rats to swim to an invisible glass platform in a circular water tank by orienting themselves to landmarks in the laboratory.
As the cholinergic neurons die, the rats lose the ability to find the platform. This memory loss is similar to that observed in Alzheimer’s disease, which affects as many as 2.5 million older Americans.
Gage had previously shown that the death of the cholinergic neurons and the loss of memory could be prevented by implanting a small pump that secreted nerve growth factor. He decided to try to produce a “biological pump” that would have the same effect.
Using a retrovirus--a highly specialized virus that can insert its own genes into the genes of an infected cell--the group inserted the gene for nerve growth factor into rat skin cells called fibroblasts. When they were grown in culture, these cells then secreted the hormone. The retrovirus was developed by UCSD molecular biologist Theodore Friedmann and his colleagues.
Gage and his colleagues then severed the fimbria-fornix in 16 rats. Eight of the rats received the engineered fibroblasts, and the other eight received normal fibroblasts.
Two weeks after the implantation, the researchers killed the rats and counted the number of cholinergic neurons that survived. In the rats that received the engineered cells, 92% of the neurons survived; in those that received normal fibroblasts, only 49% survived.
Survival Rates of Cells
“The bottom line is, we showed that the grafted cells survived and that they protected the (cholinergic neurons),” Gage said in a telephone interview. “In some animals, we had 100% savings, in others, somewhat less. But in all cases, we had more surviving cells than in the animals without engineered genes.”
Gage is now studying a new batch of rats to determine--through the swimming test--if their spatial memory is maintained by the brain graft. Gage predicted that the engineered cells would eventually be tested in Alzheimer’s patients in conjunction with other forms of therapy.
He and Friedmann are also engineering skin cells to secrete dopamine, the hormone that is deficient in Parkinson’s disease, which affects as many as 1.5 million Americans. They hope to begin testing those cells in animals soon.
Gage said it could be 10 years before the use of such engineered cells could be attempted in humans.
