Nov. 1, 1999 In an experiment that offers hope to patients with multiple sclerosis and similar disorders, scientists have managed to get transplanted brain cells to disperse and travel widely throughout the brain, according to a report in this month's Annals of Neurology, the scientific journal of the American Neurological Association and the Child Neurology Society.
The results--in a rat model of Pelizaeus-Merzbacher disease, a rare, inherited childhood disorder--are a long way from being a therapy for human sufferers, but the research is a significant first step. "It shows proof-of-principle that generalized repair may be feasible using this approach," said Ian Duncan, BVMS, PhD, a researcher at the University of Wisconsin's School of Veterinary Medicine and senior author of the report.
Multiple sclerosis (MS) and related diseases involve damage to the nerves in the brain and spinal cord. Specifically, there is a loss, or failure of development, of myelin, a substance that normally insulates the nerves and speeds electrical conduction through the fibers. In the chronic myelin disorders, cells called oligodendrocytes, which produce the myelin, are either lost or genetically impaired.
In MS, for example, depending on which nerve fibers are hindered, patients can experience problems ranging from weakness and clumsiness to numbness, visual disturbances, and even emotional and intellectual changes. Some patients experience MS as cycles of relapse and remission; others progress to severe debilitation and may die from the disease.
In diseases such as Pelizaeus-Merzbacher, where myelin does not form properly, and a number of other inherited early childhood disorders where myelin is lost (e.g., Krabbe's disease and metachromatic leucodystrophy), the consequences are almost always disastrous, with children typically dying before the age of five. Pelizaeus-Merzbacher patients are exceptions in that they occasionally survive into their twenties, frequently with severe health problems.
One suggested path to treating chronic myelin disorders is to replace the defective oligodendrocytes with new ones. Duncan's group is of several that have worked for years trying to transplant cells into the spinal cords of particular rats and dogs called myelin mutants, whose gene defects lead to myelin diseases resembling the human disorders.
"We have succeeded in myelinating large areas of the spinal cord at the site of transplantation, but generalized spread of the implanted cells has proven elusive," said Duncan.
Duncan and his colleagues, first author Randy Learish, Ph.D., of the University of Wisconsin and Promega Corporation, Inc., of Madison, Wisconsin, and Oliver Brustle, M.D., of the University of Bonn Medical Center in Bonn, Germany, decided to try an approach pioneered by Brustle and others, though not with myelin-producing cells--they implanted the cells into the brain's ventricles.
The ventricles are a series of interconnected, irregular caverns within the brain, filled with cerebrospinal fluid (CSF). The CSF has been described as a "water jacket" that surrounds and helps stabilize the brain and spinal cord. It also helps maintain a constant chemical environment and removes waste products from the nervous system.
Along the edge of these reservoirs are the brain areas where cells are born and from which they migrate into the brain to perform various specialized functions within the different subdivisions of the brain.
The researchers harvested donor cells from the brains of normal rat fetuses and injected them into the ventricles of unborn rat embryos with a Pelizaeus-Merzbacher-like disorder.
They were heartened to find that the donor cells were not only accepted by the host brains, but they dispersed throughout the ventricles, entered the brain tissue, migrated to different brain areas, and began to produce myelin.
"What was particularly exciting was that you could deliver cells simply by delivering them to this general fluid depot in the brain," said Bruce Ransom, MD, PhD, chairman of neurology at the University of Washington and editor of Glia, a journal devoted to the study of supporting brain cells such oligodendrocytes.
Duncan provides a note of caution, however. "This study does not provide an immediate therapy for human Pelizaeus-Merzbacher patients, as the amount of myelin formed in the recipient rats was insufficient to improve the function or lifespan of the mutant."
But the results do show that the difficult task of transplanting cells in a disease where the damage is widespread is theoretically feasible.
The procedure is also promising for MS, says Duncan, because many of the damaged areas in that disease are near the ventricles. He stresses, however, that this work is at a very early stage.
"We need to be able to promote migration of a greater number of cells into the brain and have them myelinate many more nerve fibers. We also need to show that we can achieve similar results in the adult brain," he said.
Another potential challenge is posed by recent evidence that the nerve cell fibers (or axons) themselves may be damaged in diseases such as MS. "We used to just think of these as naked axons that couldn't function because they had lost their myelin wrap, but the truth that has been forced on us by excellent studies in the last year or two is that the demyelinated zones have a high percentage of ruptured axons," said Ransom.
It is possible, however, that mylenation by transplanted glial cells will protect axons against further loss and that the technique may help to partially relieve some symptoms of demyelinating diseases. Ransom predicts that remyelinating techniques will ready for trials in humans in the next decade.
Su-Chun Zhang, Ph.D., of the University of Wisconsin was also an author of the report.
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