In a disease such as ALS — one that is always
fatal and that has a long history of research-
resistant biology — finding a proof of principle in
animal models is significant.
This week, Johns 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 nerves' ability to function and stave off
death significantly longer," said neuroscientist
Nicholas Maragakis, an associate professor of neurology at Johns
Hopkins, who led the research team.
"We intentionally targeted the motor neurons in this
region," he said, "since we knew that, as in ALS,
their death results in respiratory decline."
Also significant is that the transplanted cells,
called glial restricted precursors, or 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 Johns Hopkins
and elsewhere has shown their crucial role in keeping the
central nervous system 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 said. "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.
Amyotrophic lateral sclerosis is a motor neuron
disorder that affects roughly 30,000 people in
this country. It is 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
Robert Packard
Center for ALS Research at Johns 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, Christine Dejea, Andrea Pardo and
Jeffrey Rothstein, all of Johns Hopkins, and Mahendra Rao,
of the Invitrogen Corp., of Carlsbad,
Calif.
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