This is one of a series of stories in This Week on stem cell work underway at UCSD
Stem Cell Research Holds Promise
for Victims of Spinal Cord Ischemia
By Debra Kain
| March 13, 2006
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| Dr. Martin Marsala |
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Dr. Martin Marsala, an associate professor in the
department of anesthesiology, hopes his research with
stem cells will one day soon allow people who are
suffering from spinal ischemic injury to improve their
motor function.
His research focuses on is developing cell-replacement
therapies aimed at re-populating pools of inhibitory
neurons lost when blood supply to the spinal cord
is blocked during surgery. While Marsala's research
to date has been with rats and mini-pigs, his work
is moving towards human trials within the next one
to two years, with the goal of promoting motor recovery
after spinal cord ischemia.
Paraplegia from spinal cord ischemia is a serious
complication that occurs in 20 to 40% of patients
undergoing a surgical process called aortic cross-clamping.
When the surgeon works on the aorta to correct a potentially
lethal aneurysm, this large vessel carrying all of
the blood flow from the heart must be temporarily
blocked. When this clamping occurs for more than 30
minutes, the procedure can result in the loss of specialized
spinal cord neurons called spinal inhibitory neurons.
Loss of these neurons can lead to irreversible spasticity
and rigidity, or loss of muscle control, in the lower
limbs.
“The important difference between spinal cord
ischemia and spinal trauma, such as might occur in
a diving or car accident, is that no mechanical damage
has occurred to the spinal cord,” said Marsala.
“Connectivity between the spinal cord and brain
motor centers is present, but there has been a selective
loss of small inhibitory neurons in the spinal cord
that are necessary for coordinated motor activity.
Our research aims to replace these lost neurons by
grafting spinal stem cells.”
In work published in October 2004 in the European
Journal of Neurosciences, Marsala studied immuno-suppressed
rat models that were grafted with human hNT neurons.
Significantly improved motor function – measured
by a suppression of spastic movements and improved
muscle tone – was shown in 40 to 50% of the
animals.
“In short, many of the rats regained their
ability to walk due to suppression of spastic hypertonia,”
said Marsala.
During a 12-week period in which the animals were
followed, the UCSD team found that rats receiving
neuronal cell transplants displayed a progressive
recovery of motor function and a decrease in spasticity
in the lower extremities over a period of several
weeks following the injections. Fifty percent of the
animals experienced a significant improvement in motor
function. In contrast, the “control” rats
that did not receive neuron transplants exhibited
no improvement in motor function or spasticity. A
post-mortem study of the animals showed a robust maturation
of neurons and an increase in the expression of inhibitory
neurotransmitters in the spinal cords of rats that
received the transplanted neuronal cells.
“These findings provided conclusive evidence
that transplantation of human neuronal cells into
a specific region of the spinal cord can be an effective
treatment for spasticity and rigidity in cases of
ischemic spinal cord injury,” said Marsala.
Since then, the UCSD team has continued the neuronal
stem cell studies using a rat model of spinal ischemic
injury and human spinal stem cells. In addition, Marsala
recently completed pre-clinical dosing and safety
studies using mini-pigs in studies conducted in the
Czech Republic in collaboration with Dr.Jan Motlik,
a veterinarian from Institute of Genetics and Animal
Physiology in Libechov.
“We looked to find the optimal number of stem
cells to graft and to define the safety of the procedure
before moving to clinical trials using humans,”
Marsala said.
Based on the successful research results using the
mini-pigs, he and his collaborators are optimistic
of receiving permission to move ahead with these trials.
Marsala is confident that those patients affected
by spinal cord ischemia will be willing to try the
stem cell treatment. Current treatment for debilitating
muscle spasticity is continuous systemic or spinal
drug treatments using implanted pumps. These approaches,
while displaying satisfactory efficacy, are often
accompanied by side effects and eventual drug tolerance.
“This treatment offers hope to people with
spinal ischemic injury who suffer from resulting spasticity
and rigidity,” said Marsala.
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