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 fibres 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 Centre 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 fibres. 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 fibres
(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.