A must-read!

Peggy

http://www.forbes.com/forbeslife/health/feeds/hscout/2006/06/20/hscout533366
.html
Stem-Cell Therapy Restores Movement in Paralyzed Mice
06.20.06, 12:00 AM ET
TUESDAY, June 20 (HealthDay News) -- In what experts are describing as a
major advance, scientists have used embryonic stem cells to form new,
functional nerve cell connections in formerly paralyzed mice that
effectively restored the animals' limb movement.

While success in humans remains a distant goal, the achievement is "proof of
principle" that stem-cell grafts such as these might someday be used to
treat spinal cord injury, ALS (Lou Gehrig's disease), Parkinson's disease
and other crippling neurological conditions, one expert said.

"This is something that we've been looking for for 30 years," said Naomi
Kleitman, program director of the Extramural Research Program at the U.S.
National Institute of Neurological Disorders and Stroke.

Kleitman was not involved in the study, but her office helped fund the
research. She called the finding "exciting, because it proves the principle
that with the right combination, we can coax [nerve] cells out, and now we
know what to build on."

The findings will be published Monday in the journal Annals of
Neurology.

Numerous studies have come out over the past few years showing that
embryonic stem cells can form nerve cells in areas of the spinal cord
damaged by injury or disease. But getting these motor neurons to make
functional connections to muscle has been a frustrating roadblock.

"In the simplest [neuronal] relay, a brain cell talks to the motor neuron in
the spinal cord and says, 'Move that muscle,' " Kleitman explained.
"Then, the motor neuron reaches out of the spinal cord to the muscle using
these long fibers called axons. They communicate with the muscle, send an
impulse, and the muscle contracts."

But this seemingly simple network relies on a complex partnership of growth
factors and signaling chemicals -- each vital to the process. So, research
aimed at deciphering these players and their connections has continued.

"It's like a detective story where if you don't put all the clues in order,
you wind up going off in the wrong direction," Kleitman said.

The new study was conducted by a team at Johns Hopkins University School of
Medicine, led by Dr. Douglas Kerr. His group concocted a kind of neural
"recipe" that satisfied all of the conditions needed for the successful
growth and networking of new motor neurons.

Starting in the laboratory, they first used specific growth factors to spur
mouse embryonic stem cells to differentiate into motor neurons. Then they
added two chemicals -- retinoic acid and sonic hedgehog protein -- to help
these new cells feel more at home in the spinal-cord environment.

The next step was to deliver these primed cells into the spinal cords of
mice previously paralyzed by a viral infection.
But another roadblock loomed.

"We know that there are proteins in this area that inhibit axons from
growing in adult animals," Kleitman explained. The proteins are linked to
the protective myelin sheath that coats nerve fibers. "They're part of how
we keep our nervous system from going haywire during normal function," she
said.

To overcome this resistance, the Hopkins team added two agents -- cyclic AMP
(cAMP) and the drug rolipram -- to the mix. According to Kleitman, these
molecules "block the 'stop sign,' so that now the axons can grow."

But there was one more hurdle -- it's one thing to allow axons the freedom
to grow, but to grow where? "You've got pretty long distances to cover, so
one of the things you need is a 'target' that's screaming out like a neon
sign, 'Come here!' " Kleitman said.

The Hopkins group created just such a target by applying a powerful neural
growth factor, called GDNF, to the remains of nearby, deadened sciatic nerve
cells. The GDNF -- derived from fetal mouse neural stem cells -- essentially
"called out" to the growing axons, urging them to make the connection.
In the end, this complex biochemical "recipe" worked, the Hopkins team
reported.

Of the more than 4,100 new motor neurons created in one mouse's spinal cord,
about 200 exited the cord and 120 found their way to skeletal muscle. These
new connections looked identical under the microscope to those seen in
healthy mice, the researchers said.
What's more, 11 of the 15 treated, previously paralyzed mice began to regain
muscle strength and function and were more mobile in their cages.

However, this restoration of function did not occur when the researchers
left out even one of the ingredients from the mix.
According to Kerr, his team has simply tried to recreate the environment
that directs neural formation early in fetal development.

"As adults, our cells no longer respond to early developmental cues because
those cues are usually gone," he explained in a statement. "That's what we
believe we have changed [here]. We asked what was there when motor neurons
were born, and specifically what let motor neurons extend outward. Then we
tried to bring that environment back, in the presence of adaptable,
receptive stem cells."

Kleitman called the work "elegant," but stressed that much more research
needs to be done before this strategy could be applied to human patients.
"To take this to a person you need to work with something larger than a rat
leg -- that's only about an inch of [neuronal] growth," she said. Scientists
also need to make sure that certain risks associated with stem-cell therapy
-- most notably, increased tumor formation -- can be minimized.

However, Kerr said his group is already engaged in a federally funded study,
set to start this summer,that will try and replicate the mouse findings in a
larger model -- a pig -- using human embryonic stem cells. If that effort
proves successful, FDA-approved human clinical trials might be a few years
away, the researcher said.
Kleitman said the new advance has everyone in her field optimistic.

"We get really excited when good science leads to more good science, that
then leads in a direction that can really help people," she said.

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