Combination Therapy Leads to Partial
Recovery from Spinal Cord Injury in Rats
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. |