Source:
Nature 435, 877-878 (16 June 2005) |

Stem-cell therapies:  The first wave
Catherine Zandonella1

When patients with the paralysing illness amyotrophic lateral sclerosis
(ALS) call Jennifer Brand to ask when stem-cell therapies will be
available, she has a stock answer. Brand, who is director of patient
services for the California-based ALS Association, says that stem-cell
research is still in its infancy. It's just too soon to tell when it
might move into clinical trials, she tells her callers.

Ready to use? Stem cells may be able to protect depleted nerve cells
(above), kill brain tumours or help heal damaged heart muscle.
Indeed, most experts predict that many years of laboratory work will be
needed before stem cells can be used reliably to replace damaged cells
and tissues. But some enthusiasts argue that this timeline overlooks more
immediate clinical opportunities. These researchers want to exploit stem
cells' abilities to home in on sites of injury and to deliver
biochemicals that protect other cells1. And, controversially, they hope
to move quickly into the clinic. "Disease targets thought to be far in
the future are closer to our grasp," claims Evan Snyder, who works at the
Burnham Institute in La Jolla, California.

Stem cells have been widely touted as eventual cures for
neurodegenerative diseases such as ALS and Parkinson's. The conventional
wisdom is that they would be grown to produce the particular nerve cells
that are lost in each disease, which would then be grafted into the
nervous system to repair it. But researchers currently understand little
about the signals that make stem cells differentiate into particular cell
types, nor are they sure how to get grafted cells to integrate
effectively into tissues and organs.

Snyder agrees that cell replacement is an exciting future prospect. But
apart from replacing lost cells, he notes that stem cells have other,
more subtle roles that could be exploited therapeutically. Snyder has
evidence that, in the nervous system, stem cells can act as 'chaperones'
that nurse sick and injured neurons back to health.

Neural stem cells secrete biochemicals that make the neurons function
better, promote survival, decrease inflammation and encourage the growth
of blood vessels. One of these factors is glial cell line-derived
neurotrophic factor, or GDNF — which seems to protect both the cells that
secrete the neurotransmitter dopamine2, lost in Parkinson's disease, and
the motor neurons that are destroyed in ALS (ref. 3).

Snyder has shown that neural stem cells taken from mouse fetuses secrete
GDNF and promote recovery in mouse models of Parkinson's disease4. More
recently, his team has found that human neural stem cells, from lines
originally derived from the brains of aborted fetuses, can migrate from
one side of a mouse's brain to the other in response to distress signals
issued by injured tissue5. The potential to exploit these twin effects
therapeutically is clear, Snyder argues. "You are not trying to replace
the lost cells," he says. "Instead, you are trying to protect what is
there."

Other researchers are working along similar lines — but are tweaking
their cells genetically to make them into better nursemaids. At the
University of Wisconsin, Madison, Clive Svendsen's team has engineered
fetal neural stem cells so that they pump out greater quantities of GDNF.
When the researchers injected these cells into the spinal cords of rats
suffering from an ALS-like disease, they survived well and continued to
secrete GDNF (ref. 6).

Taking the chance
Svendsen plans to approach the US Food and Drug Administration within the
next few months to discuss testing the cells in ALS patients. He believes
that the ideal time to give the treatment will be shortly after
diagnosis, when a patient begins to lose limb function but before
paralysis sets in. "You have a window of about a year-and-a-half to get
in and do something," Svendsen argues. Although he hasn't yet published
firm evidence from animal experiments that shows his engineered cells are
protecting motor neurons, Svendsen has few doubts about pressing ahead
into the clinic with a novel experimental therapy — given the severity of
the disease and the lack of any effective treatment.

Similar risk-benefit arguments apply for patients with inoperable brain
tumours. Here, too, some researchers are thinking about using genetically
engineered stem cells. "The advantage is that these cells can track down
and migrate through the tumour," says Frederick Lang, a brain surgeon at
the University of Texas M. D. Anderson Cancer Center in Houston. His team
has taken cells from bone marrow known as mesenchymal stem cells and
inserted a gene for interferon- — a protein that can kill tumour cells.
When the researchers injected the cells into the carotid artery of mice
suffering from brain cancer, the cells migrated to the tumour.
Encouragingly, these animals lived significantly longer than those who
received injections of normal cells7.

You are not trying to replace the lost cells. Instead, you are trying to
protect what is there.

Heart of the matter
Lang's approach may offer hope for patients who have no other treatment
options, but many stem-cell researchers are alarmed about trials for
patients with heart disease that are already under way. Based on
contested results from animal experiments8, clinicians in the United
States and Europe are now injecting stem cells into patients' damaged
hearts in the hope that they will help repair the damaged tissue.

The problem is that nobody knows for sure whether these cells are
differentiating into heart muscle cells, fusing with cells that are
already there, or exerting a protective effect by secreting growth
factors. It could be a combination of all three, says Emerson Perin, who
is heading a study of bone-marrow stem cells injected directly into
patients' diseased hearts at the Texas Heart Institute of St Luke's
Episcopal Hospital in Houston.

Given the limited understanding of how stem cells behave when injected
into the body, some researchers argue that it is too soon to be entering
the clinic. For instance, Roger Barker, a neurologist at the Centre for
Brain Repair at the University of Cambridge, UK, worries that neural stem
cells might give rise to neurons that could integrate incorrectly into
the nervous system, causing adverse effects such as a heightened
sensitivity to pain. If so, he fears that the resulting publicity could
damage the entire field. "A negative trial doesn't do any good," says
Barker.

Snyder agrees that caution is necessary, but he argues that early trials
using stem cells as nursemaids to protect sick and dying tissues will do
the field a service, by giving the regulators and institutional review
boards that must approve clinical trials some experience of handling
stem-cell protocols. This will blaze a trail for later trials with the
loftier goal of replacing damaged tissues, Snyder claims.

In any case, Snyder believes that the risks are relatively constrained
for stem cells derived from fetal or adult tissues, provided they are
used only in the places where they would normally be found. If cells
aren't being put in alien tissues, he argues, they are likely to behave
normally.

Growing pains
But embryonic stem cells, which can develop into any of the body's
tissues, are another matter. In particular, they can form tumours called
teratomas that contain all sorts of tissue types. "You don't want bone or
teeth or hair growing inside the spinal cord," says Svendsen. "It just
wouldn't look good for the stem-cell field." Nevertheless, some
researchers are exploring the idea of using embryonic stem cells to exert
nursemaid effects. They note that the cells could be engineered to
include a 'suicide' gene that could be activated to kill them, if any
problems arise.

Robert Benezra of the Memorial Sloan-Kettering Cancer Center in New York
and his colleagues are studying a genetic condition that normally causes
female mice to lose their young before birth because of heart defects.
When Benezra's team injected pregnant females with mouse embryonic stem
cells, they gave birth to live young9. The stem cells didn't cross the
placenta, but they secreted a heart-repairing substance called
insulin-like growth factor 1, which seemed to protect the fetuses.

Benezra has no plans to move ahead into clinical trials. But cells grown
directly from embryonic stem cells could start being injected into
patients with paralysing spinal injuries as early as next year. Hans
Keirstead, a stem-cell researcher at the University of California,
Irvine, has derived cells that seem to restore some mobility to rats with
spinal injuries10. These cells make the myelin protein coat that serves
as electrical insulation for neurons — although Keirstead suspects that
other protective mechanisms are also involved. "I believe that they are
playing some mysterious 'nurse' role," he says. "They are doing a lot
more than just producing myelin."

Keirstead's plan to move rapidly into the clinic has already caused some
alarm11. But with other trials of stem cells as nursemaids for sick and
dying cells also in the works, patient advocates such as Brand may soon
have to revise their message. With luck, these trials will bring fresh
hopes for the sufferers of ALS and other debilitating conditions — and
not scare stories about adverse reactions.

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Aldhous P. Nature 434, 694-696 (2005). | Article | PubMed | ChemPort |
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