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New Pathways Studied to Repair Nerves

THURSDAY Nov. 6, 2008 -- Nerve cells in the spinal cord and brain can't be repaired now if they are severed or damaged, but two ways to get them to grow again are being proposed by separate groups of researchers.

The basic idea of both approaches is to interfere with the built-in mechanisms that prevent nerve cell regeneration. One approach attacks it from the outside of nerve cells, the other from the inside.

Zhigang He, an associate professor of neurology at Children's Hospital Boston, a teaching affiliate of Harvard University, compared the two approaches to different ways of starting a stalled auto.

"Their idea is that something is blocking the highway," said He, lead author of one of the two papers in the Nov. 7 issue of Science. "Our mechanism deals with possible engine trouble."

Growth controls are built into the genes of nerve cells, He said. His group has identified two of the key genes that inhibit the major growth pathway in nerve cells. When those two genes are knocked out, cells that are damaged or severed can grow new axons, the pathways that carry messages from cell to cell.

A study in which mice whose optic nerves were damaged showed up to 50 percent of those cells engineered to lack the two growth-inhibiting genes survived, compared to 20 percent of the cells carrying those genes. Significant axon growth was seen in up to 10 percent of the mice lacking the genes.

Genetic engineering is not necessary to achieve that kind of nerve growth, He said. "In the future, we could have small-molecule drugs to activate these pathways," He said. "Other people have studied this pathway already, and there are quite a few possible targets."

He's group has started to work with some candidate compounds. "It's too early to say if these compounds would be effective," he said. "We don't know about toxicity, that sort of thing. We have lots of work to do."

A second paper by researchers at the San Francisco-based biotechnology company Genentech looked at the growth-preventing mechanism built into myelin, the protective sheath that surrounds nerve cells. They have identified a previously unknown receptor for the growth-preventing molecules in myelin. Block that receptor, and growth can be restored, said Marc Tessier-Lavigne, executive vice president of research drug discovery at Genentech.

"This is a mechanism we can try to target," Tessier-Lavigne said. The paper describes a molecule that has blocked the receptor in mice. "Now we are working on a human protein."

Both approaches require more work, said Dr. William D. Snider, director of the University of North Carolina Neurosciences Institute, and co-author of an accompanying editorial.

The idea of blocking growth-preventing genes "is a very clever way of restoring normal levels of proteins," Snider said, but he was cautious, because all the work reported in the paper was done in mice.

"Mice are extremely small animals when you compare their nervous systems to humans," Snider said. "Work in primates might be more relevant. Those of us who have been in the field for a while are extremely cautious about extrapolating from mice."

The Genentech myelin approach is not new, Snider noted. "People have known in general that myelin down-regulates nerve cell growth capacity, although they're not certain why that is true," he said. One belief is that the myelin mechanism is designed to prevent errors at times when there is a major change in the central nervous system. Knowledge of a new receptor that governs nerve cell growth could be of practical value, Snider said.

More information

The workings of nerve cells are explained by the U.S. National Institute of Neurological Disorders and Stroke.

Posted: November 2008


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