Targeted Cell Delivery To The Cervical Spinal Cord Is A Promising Strategy

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Targeted Cell Delivery To The Cervical Spinal Cord Is A Promising

Strategy To Slow Loss Of Motor Neurons In ALS

http://www.medicalnewstoday.com/articles/126100.php

21 Oct 2008

In a disease like ALS - one that's always fatal and that has a long

history of research-resistant biology - finding a proof of principle

in animal models is significant.

This week, s Hopkins researchers report that transplanting a new

line of stem cell-like cells into rat models of the disease clearly

shifts key signs of neurodegenerative disease in general and ALS in

particular - slowing the animals' neuron loss and extending life.

The new work supports the hypothesis that artificially outnumbering

unhealthy cells with healthy ones in targeted parts of the spinal

cord preserves limb strength and breathing and can increase survival.

An account of the work appears online this week in Nature

Neuroscience.

Two parts of the study hold special interest: One is that the target

area for the added cells - parts of the cervical spinal cord that

control the diaphragm muscles largely responsible for breathing -

reap the most benefit. Forty-seven percent more motor neurons

survived there than in untreated model animals. Respiratory failure

from diaphragm weakness is the usual cause of death in ALS, also

called Lou Gehrig's disease.

" While the added cells, in the long run, didn't save all of the

nerves to the diaphragm, they did maintain its nerve's ability to

function and stave off death significantly longer, " says

neuroscientist Maragakis, M.D., an associate professor of

neurology at s Hopkins who led the research team.

" We intentionally targeted the motor neurons in this region, " he

says, " since we knew that, as in ALS, their death results in

respiratory decline. "

Also significant is that the transplanted cells, called glial

restricted precursors (GRPs), address a well-known flaw in people

with ALS and in its animal models. Both humans and models are stunted

in their ability to clear away the neurotransmitter glutamate. And

excess glutamate - common in ALS - overstimulates the motor neurons

that spark muscle movement, causing death. The event, called

excitotoxicity, also occurs in other neurological diseases.

So on a more basic level, the study adds clout to the principle - in

live animals - that excitotoxicity is a major bad guy in ALS and that

finding more effective ways to avoid or lessen it could help protect

the nervous system.

In their research, the team transplanted some 900,000 glial

restricted precursors overall to specific sites in the cervical

spinal cord of each model rat in early stages of disease. The GRPs

the scientists used began life as what's called astrocyte progenitor

cells from healthy rat spinal cord tissue. Following transplant, they

transformed into mature, healthy astrocytes, found living alongside

sick motor neurons.

Astrocytes are the most common cells in the central nervous system.

Work at s Hopkins and elsewhere has shown their crucial role in

keeping the CNS in healthy balance. Not only are the cells studded

with transporter molecules that mop up glutamate; they also maintain

proper ion levels and nutrient support of nerve cells.

The study showed that at least a third of the added GRPs " took root "

after their transplantation. With time, almost 90 percent of the GRPs

had differentiated into astrocytes. Unlike the model rats' own

astrocytes, the new ones continued to appear healthy. None of the

GRPs damaged the spinal cord or formed tumors - a worry with some

stem cell therapies.

Transplanting alternate GRPs - those that the team engineered to lack

glutamate transporters - offered none of the protective properties.

" Our findings demonstrate that astrocyte replacement, by

transplantation, is both possible and useful, " Maragakis

explains. " This targeted cell delivery to the cervical spinal cord is

a promising strategy to slow that loss of motor neurons in ALS. We

hope at some point that these principles will translate to the

clinic. "

Earlier research by U.S. scientists suggests that, while astrocytes

go downhill in ALS, they may not be a primary cause of the disease.

The idea is more that they're involved in its progression. Diseased

astrocytes, studies show, may make motor neurons more susceptible to

death by excitotoxicity.

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Article adapted by Medical News Today from original press release.

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Amyotrophic lateral sclerosis (ALS) is a motor neuron disorder that

affects roughly 30,000 people in this country. It's characterized by

a rapid decline in motor neurons, with death from respiratory failure

typically occurring from two to five years after diagnosis.

Principal researchers in this study are members of the Packard

Center for ALS Research at s Hopkins, which funded the work along

with grants from the ALS Association and the National Institutes of

Health.

The research team included Angelo Lepore, Britta Rauck,

Dejea, Pardo and Rothstein, all of s Hopkins, and

Mahendra Rao with the Invitrogen Corp., of Carlsbad, Calif.

On the Web: http://www.alscenter.org/

Source: alice Yakutchik

s Hopkins Medical Institutions