| July 25,2005 - Combining partially differentiated stem cells with gene therapy can
promote the growth of new "insulation" around nerve fibers in the
damaged spinal cords of rats, a new study shows. The treatment, which
mimics the activity of two nerve growth factors, also improves the
animals' motor function and electrical conduction from the brain to the
leg muscles. The finding may eventually lead to new ways of treating
spinal cord injury in humans. The study was funded in part by the
National Institute of Neurological Disorders and Stroke (NINDS), part of
the National Institutes of Health.
The new study provides the best demonstration to date that producing
a nerve-insulating substance called myelin can lead to functional
improvements in animals with spinal cord injury. Previous studies have
shown that the loss of myelin around nerve fibers contributes to the
impaired function after a spinal cord injury. However, until now it has
not been clear whether promoting new myelin growth in the spinal cord
can reverse this damage, says Scott R. Whittemore, Ph.D., of the
University of Louisville in Kentucky, who led the new study. "Many other
investigators have suggested that remyelination is a possible approach
to repair the spinal cord, but this is the first study to show
unequivocally that it works," says Dr. Whittemore. "It is a proof of
principle." Although the finding is promising, much work remains before
such a technique could be used in humans. The study appears in the July
27, 2005, issue of the Journal of Neuroscience.1
In the study, the researchers took special cells called glial-restricted
precursors from the spinal cords of embryonic rats. These precursor
cells develop from stem cells and are specialized so that they can form
only two kinds of cells: astrocytes, which help support neurons and
influence their activity, and oligodendrocytes, which produce myelin.
The scientists used a modified virus to insert genes for marker proteins
that make the cells visible. Some cells also received a gene called
D15A. This gene produces a protein with activity similar to growth
factors called neurotrophin 3 (NT3) and brain-derived neurotrophic
factor (BDNF). Both NT3 and BDNF help myelin-producing cells (oligodendrocytes)
develop and survive.
Dr. Whittemore and his colleagues injected the treated precursor
cells into the spinal cords of rats with a type of spinal injury called
a contusion, which is caused by an impact to the spinal cord. Other
groups of spinal cord-injured rats received just precursor cells, D15A
gene therapy, or other treatments that were used for comparison. The
rats were evaluated weekly for 6 weeks after the treatment using a
behavioral test called the Basso-Beattie-Bresnahan scale, which measures
characteristics such as weight support, joint movements, and
coordination. The researchers also used an electrical current test in
which they put a magnetic stimulator on the skull and measured whether
the resulting electrical current was transmitted to a muscle in one of
the hind legs.
Most of the rats treated with the combination of precursor cells and
gene therapy improved significantly on both tests, the researchers
found. The combination therapy led to an improvement in the rats'
ability to walk and about a 10 percent improvement on the electrical
current test. Rats that received the other treatments did not improve
significantly, and untreated rats did not have any electrical activity
that passed through the damaged spinal cord. Studies of the damaged
spinal cord tissue after the combined treatment showed that many of the
transplanted cells survived and migrated within the cord and that about
30 percent of them developed into myelin-producing oligodendrocytes.
"The key word here is 'combination.' This is one of a series of new
studies showing that a combination of therapies is needed for successful
spinal repair, in this case, specialized cells and growth factors. The
experiments also used a combination of outcomes — physiology, behavior,
and anatomy — to point clearly at myelination as the cause for improved
function," says Naomi Kleitman, Ph.D., the NINDS program director for
the grants that funded this work. "The study also is a good example of
strong collaboration between two spinal cord injury research centers,
one at the University of Louisville and the other at the University of
Miami in Florida."
The researchers are now investigating ways to improve this type of
therapy with additional genetic modifications to the transplanted cells,
and they plan to test similar techniques that start with
undifferentiated embryonic stem (ES) cells instead of glial-restricted
precursor cells. ES cells would be better for human studies than glial-restricted
precursors because ES cells can be more readily obtained, Dr. Whittemore
says.
The NINDS is a component of the National Institutes of Health
within the Department of Health and Human Services and is the nation’s
primary supporter of biomedical research on the brain and nervous
system.
The National Institutes of Health (NIH) — The Nation's Medical
Research Agency — is comprised of 27 Institutes and Centers and is a
component of the U. S. Department of Health and Human Services. It is
the primary Federal agency for conducting and supporting basic,
clinical, and translational medical research, and investigates the
causes, treatments, and cures for both common and rare diseases. For
more information about NIH and its programs, visit
www.nih.gov. |