Are We There
Yet?
The Rocky Road to Stem Cell Therapies for ALS
by Margaret Wahl
John Winchester of Medina, Ohio, learned he had ALS in 2001, and
by late in 2004 felt that time was no longer on his side. When he
learned stem cells were being used to treat ALS in China, he decided
to take the treatment whatever the risk (see “Beijing
Report,” October-November).
In Van Buren, Ark., this summer, John Riggs, whose ALS was diagnosed
in 2002, and his wife, Gaye, made the same decision, as did Willie
Terpstra, a Rotorua, New Zealand, woman with ALS, who returned from
China in April.
All three were treated in a Beijing Hospital, and all received
cells from the part of the brain involved in the sense of smell
(olfaction), taken from fetuses. Doctors inserted these olfactory
ensheathing cells directly into the brains of the patients, after
drilling holes in their skulls under local anesthesia.
And, all three tell a similar story: improvement at first, then
gradual loss of function over the ensuing weeks. Did the cells do
any good, even temporarily, and if so, how? These are the questions
researchers are trying to answer.
A Natural Repair Process
Until about a decade ago, the accepted wisdom was that there were
no cells in the human central nervous system (the brain and spinal
cord) that could replace those killed by disease or injury.
Then, in 1994, scientists found precursors of nerve cells (neurons)
in the human brain. The stem cells were few, but they were there,
in the areas bordering the fluid-filled spaces in the brain known
as ventricles and in the memory consolidation area, the hippocampus.
Although it wasn’t very effective at damage control, one
thing was clear: Like many other tissues, the central nervous system
had replacement parts and a mechanism for using them.
Almost immediately, neuroscientists began thinking about using
neural stem cells to treat disease, but where to get them was a
problem.
Unlike muscle tissue, which has a ready supply of “satellite”
muscle cell precursors that can be donated by family members, the
nervous system has no such supply — and, even if it did, people
wouldn’t want to donate cells from their brains or spinal
cords.
Human embryos and fetuses are an obvious possibility, since their
cells are in a very early stage of development and could presumably
be coaxed along a desired pathway. But, in addition to the ethical
controversies surrounding their use and funding restrictions on
this research in the United States, it isn’t clear that these
completely flexible stem cells would be the best to use anyway.
They might, if used before we fully understand them, form the wrong
kind of cell.
Bone Marrow Offers Hope
Among the other sources of neural progenitors are bone marrow stem
cells.
In 2003, Italian researchers reported transplanting marrow cells
taken from ALS patients’ own pelvic bones into their spinal
cords. The study was designed only to test the feasibility and safety
of the procedure, and it passed those tests. No benefits were seen.
In Houston, about the same time, neurologist Stanley Appel, who
directs the MDA/ALS center at the Methodist Hospital, infused donated
bone marrow cells into the veins of six people with ALS. Only two
of the six survive, and Appel can only speculate about what, if
any, effects the cells might have had, although he suspects the
immune system is involved.
Umbilical Cord Blood Shows Promise
Embryonic cells may be too flexible and ungovernable for use right
now, and cells from bone marrow that might be suitable for a nerve
cell path are too few for a disease that covers a large part of
the nervous system.
But blood left in the umbilical cord after a baby’s birth
could harbor effective, noncontroversial cells.
When scientists at the University of South Florida gave mice destined
to develop a genetic form of ALS an intravenous infusion of human
umbilical cord blood cells, they found some of the new cells migrated
to the brain and spinal cord, and the treated mice survived longer
than the untreated ones.
Replacement or First Aid?
Replacing motor (movement-related) neurons in a disease that affects
most of the central nervous system is a daunting task. Expecting
new cells to populate the CNS in adequate numbers, and then to make
the intricate connections to muscle and other cells once there,
may be asking too much.
Even if some of the new cells made it to the right place and made
the right connections, it seems likely that the same mysterious
process that killed the ALS patient’s own neurons would take
out the new cells, too.
But replacement of neurons isn’t the only route to ameliorating
ALS with new cells. In 2003, researchers in the laboratory of Jeffrey
Rothstein, director of the MDA/ALS center at Johns Hopkins University
in Baltimore, observed that when rats paralyzed by a virus were
given human embryonic stem cells, most of the new cells didn’t
become neurons.
However, they appeared to do something that allowed the animals
to partially recover motor function.
It seems they secreted “nerve-nourishing” substances
called neurotrophic factors that apparently kept many of
the rats’ own motor neurons alive.
This type of first aid for cells, sometimes called trophic support,
is easier to contemplate than total CNS replacement. “There
are multiple nourishing factors that are active on motor neurons,”
says Vassilis Koliatsos, an MDA grantee at Johns Hopkins. “Based
on work in our and other labs this past year, many of these factors
— including some called BDNF and GDNF — are manufactured
by neural stem cells.”
Drugs Versus Cells
Koliatsos thinks it may be time to move away from the search for
“magic bullet” compounds in a disease where “we
hardly know what’s going on in the vast majority of patients,”
and pay more attention to whole cell approaches. “The infectious
disease model of targeting microbes with selective compounds may
not be the right model for neuro-degenerative diseases,” he
says.
But finding the right cells is essential. “We have seen unacceptable
side effects, such as increased pain sensation, from cells that
lack specificity,” he says. For Koliatsos, only “long-term,
hugely successful experiments in long-living animal models, with
no tumor formation” would justify clinical trials of putative
stem cells in ALS.
Back to top
Jeanine Schierbecker
— Physical Therapist
by Kathy Wechsler
Jeanine R. Schierbecker of St. Louis has been a physical therapist
(PT) at Washington University School of Medicine’s MDA clinic
since 1985, 11 years before it was designated an MDA/ALS center.
A Team Approach
Schierbecker’s one of four PTs working in the MDA/ALS center,
which is one of the clinics under the direction of the department
of neurology.
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Physical therapist Jeanine Schierbecker tests the strength
of ALS patient Glen Houston, who was in a clinical trial
at Washington University.
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“When the doctor walks in the room and says, ‘This
is the problem the patient is having,’ we all jump in and
try to address that problem to the best of our abilities,”
she said. “If we feel that it exceeds our skills, then we
make sure we get the right person involved.”
Every day’s different for Schierbecker. From showing a caregiver
how to stretch a tight joint to teaching a family member the correct
method of transferring, there’s a lot of educating involved
in her position. She works with patients and their families to solve
mobility issues.
Another part of her position is to help recognize when special
dietary changes are necessary for those who are having trouble chewing
and swallowing. Sometimes it’s something simple like thickening
liquids or changing the texture of food. Other times it requires
the expertise of a dietician, and the clinic’s dietician is
called in to evaluate the patient’s needs.
Schierbecker enjoys being a resource for people with ALS and their
families and helping them find the answers to their questions.
She received her education at Washington University, earning a
bachelor’s degree in PT in 1982 and a master’s in health
science in 1992.
“I tend to think in a mechanical way. The human body is kind
of the ultimate machine, if you will,” Schierbecker said.
“Figuring out how everything works — and when it doesn’t
work how can you make it work again, or, what can you do instead
— is probably what intrigued me the most about physical therapy.
“Because there’s no occupational therapist (OT) within
the neuromuscular division, we put on our OT hats once in a while,
too,” said Schierbecker.
When she’s wearing her “OT hat,” Schierbecker
runs down her list of questions about activities of daily living
such as feeding, dressing, bathing and toileting to see if she can
make any suggestions. She recommends assistive devices.
“We’ve found that an in-home assessment by an OT is
invaluable and usually more ‘real’ than what we are
able to do in a clinical setting,” she said. “We’re
fortunate that our OT program at WU has a community outreach program
that provides in-home assessments.”
Clinical Trials
Besides her work in the neuromuscular outpatient clinic, Schierbecker
is involved in the clinical drug trials unit within the neuromuscular
division.
Since she’s familiar with patients from clinic, Schierbecker
assists in finding and recruiting subjects for the clinical trials.
She offers participation to every patient who meets the criteria
of any particular study.
“When we start a study, we take advantage of that dual role
and say, ‘By the way, I don’t know if you are interested
in a clinical trial or not, but this is what we are going to be
doing in the near future,’” she said. “If we’re
not ready to start enrolling, we at least share what information
we have, take their names and call them when we are up and running.”
Schierbecker is also a clinical evaluator in the clinical trials
unit. A clinical evaluator assesses the patient, usually including
an assessment of the person’s strength before and after the
ALS treatment in question, and provides the data derived from the
assessment for the study’s primary and secondary outcomes.
“Whenever you’re doing any kind of clinical trial research
in [the ALS] population, what you are hoping for is an improvement
in strength, or a slowing of the progression of the disease, ”
Schierbecker said. “It’s really critical that your clinical
evaluator understand all the nuances of muscle testing and strength
assessment involved in these trials. So much of our physical therapy
education focuses on assessing movement and strength, so it’s
a great use of our education and clinical skills.”
Above and Beyond
Schierbecker’s duties extend well beyond the neuromuscular
clinic and ALS clinical trials.
Involved in various local MDA support groups, including two support
groups concerning the issues of living with ALS, she often speaks
about physical therapy issues of interest to the group and answers
questions about exercise, mobility, body mechanics and equipment.
Sometimes she visits school districts and speaks with school therapists
who work with children in the school system.
This summer was Schierbecker’s 20th year as a volunteer at
the St. Louis-area MDA summer camp held at Babler State Park Outdoor
Education Center in Chesterfield, Mo.
Since Schierbecker’s on the summer camp planning committee,
she gets to help pick each year’s camp theme and decide on
camp activities.
“It’s fun for me because the kids respond to me differently
at camp than they do in clinic. In clinic, I am part of the white-coat
team, but at camp I’m just a volunteer.
“It creates a different dynamic that I think helps me be
a better clinician when I see them outside of camp; they feel more
comfortable and might share more with me in clinic.”
Back to top
ALS Research Roundup
by Margaret Wahl
Arimoclomol Multicenter
Trial Set to Begin
A multicenter clinical trial of the experimental compound arimoclomol,
developed by CytRx (www.cytrx.com),
a Los Angeles biopharmaceutical company, is set to begin testing
in people with ALS during the first half of 2006.
Arimoclomol is a small molecule that’s designed to stimulate
a natural cellular repair pathway by activating compounds called molecular chaperones. It has been shown to extend life in
ALS-affected mice and was well tolerated in healthy human volunteers
in a recently completed, phase 1 study.
CytRx received a green light for a large-scale, phase 2 study from
the U.S. Food and Drug Administration on Sept. 21 and has begun
identifying potential trial participants at some of its sites. The
FDA has also granted arimoclomol “fast-track” status,
a program begun in 1997 to hasten review of potential treatments
for serious or life-threatening diseases.
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Francois Berthod and student Marie Gingras are developing
a model of the nervous system in a Quebec lab.
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The principal investigators for a 12-week, 80-patient, phase 2a
study are Robert Brown, who directs the MDA/ALS center at Massachusetts
General Hospital; Merit Cudkowicz, an MDA research grantee and MDA-associated
clinician at that institution; and Jeremy Shefner, director of the
MDA/ALS center at SUNY Upstate Medical University in Syracuse, N.Y.
The study is likely to take place at eight to 10 U.S. sites. Participants
will receive either a placebo (inactive substance) or one of three
arimoclomol dosage levels.
Depending on the results of the phase 2a study and FDA approval,
an 18-month, phase 2b study, with approximately 300 participants
at 25 sites, is planned.
For more information, call (617) 726-9122, a
clinical trials center at Massachusetts General Hospital.
Canadian Group Recreates
Cellular Neighborhoods
A research group including MDA grantees Francois Berthod at Laval
University and Saint-Sacrement Hospital in Quebec and Heather Durham
at Montreal Neurological Institute is developing a three-dimensional
model of the nervous system. The model, they say, has advantages
over traditional approaches to growing cells in the laboratory and
over studying nerve cells in a human or animal body.
The former, Berthod says, doesn’t adequately mimic the environment
in which nerve cells normally exist, and the latter involves so
many variables that it can be impossible to sort out specific causes
of nerve cell degeneration or protection.
The new three-dimensional model, based on techniques Berthod learned
while perfecting nerve fiber regeneration in lab-grown skin developed
to treat patients with burns, includes not only motor neurons (the
muscle-controlling nerve cells that die in ALS), but all other cells
normally found in the vicinity. These include sensory nerve cells,
inflammatory cells (microglia), supportive cells, myelin-producing
cells, and cells found in connective tissue and blood vessels.
“We will test one or two cell types at a time until we see
motor neuron death,” said Marie Gingras, a graduate student
in Berthod’s lab. The team aims to use the model to isolate
specific ALS-causing mechanisms and test potentially therapeutic
drugs.
“If the cells die from adding microglia, then we know that
is a disease origin,” Berthod said, adding that blood vessel
cells, which haven’t received much attention in ALS studies,
could also have an impact. In the nervous system of a whole animal,
he says, “masking effects” of regulatory mechanisms
are “always a risk.”
2005
— The Year of Hurricanes
by Christopher and Reda Rice
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Chris and Reda Rice of Houston are
co-chairs of MDA's ALS Division
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In a year filled with two devastating hurricanes, we’re reminded
that many families live with their own hurricane each day —
and its name isn’t “Katrina” or “Rita”
(and, hopefully, our family wouldn’t call it “Reda”).
Its name is ALS.
Crashing out of nowhere, ALS changes our lives. We are going about
our life, minding our own business and doing our best, when all
of a sudden, the wind starts blowing and doesn’t seem to let
up … at least for a while. It can gain speed fast, and if
we are not careful, wreck everything in its path — our families,
our hope, our attitudes and ultimately, our entire life.
What We Can Learn
We would all be wise to take notes from our fellows and friends
in the Gulf Coast area who, during the most challenging times of
their storm, reached out to one another in support and love.
Learn earnestly from those who continue to live, moving on and
adjusting to their new surroundings. They know they aren’t
running a sprint in the recovery of their cities, jobs, houses and
lives. This is a marathon that will take endurance, patience and
hope.
Graciously, they accept help from family, friends and organizations
that specialize in natural disasters, knowing there is no room for
pride. Many hang on to their faith and trust in their God.
For those of us facing the hurricane of ALS, may we remember to
lean on one another, knowing that support is imperative. May we
go to organizations specializing in ALS and accept guidance and
help. May we run our marathon to the best of our ability, training
our minds, not our muscles, in order to complete the race. For in
our storm, it is our positive attitude and hope that must endure
to the finish line.
May your 2006 be full of hope, love, help, laughter and happiness.
May your storm be just a part of your life and not rule it. And
may God’s blessing be with you.
Back to top
The Time It Takes To Make Time Is Worth the
While
by Christina Medvescek
Does this imaginary conversation sound familiar?
Expert Advice Giver (EAG): (pompously)
Caregivers must take time for themselves on a regular basis
to maintain the physical and mental health necessary to do their
demanding jobs.
Caregiver: (snorts) Yeah, right. Time off
doesn’t just happen — it takes planning, scheduling,
and training somebody new. Who has time for that?
EAG: (earnestly) But not taking time off
may end up costing you more time and difficulty in the long run.
Unrelieved caregiver stress has been implicated in weakened immune
function, back pain, anxiety, depression, heart strain, memory loss,
overeating, sleeplessness, exacerbation of existing medical conditions,
impaired healing …
Caregiver: (brusquely) Yes, yes —
but I’m fine. Really. I can handle it all: the caregiving,
a job, the family, the housework, reshingling the roof. I’m
tougher than I look.
EAG: Well, if you won’t do it for yourself,
do it for your loved one. According to the National Family Caregivers
Association (NFCA), more people enter nursing homes because their
caregivers suffered from burnout than because their own condition
worsened. And a 1999 study published in the Journal of the American
Medical Association found that stressed-out elderly spousal caregivers
with their own history of chronic illness had a 63 percent higher
mortality rate than similar noncaregiving peers. Ask yourself: Who
will provide my loved one with care if I’m no longer around?
Caregiver: But...but…it will cause me even
more stress finding somebody I trust to stay with my loved one while
I get away. And then I have to train that person in all the special
routines and procedures. And then my loved one probably would hate having a stranger around anyway — so no, it’s just easier
to do it all myself.
EAG: What about asking family for help?
Caregiver: (bitterly) Ha! Don’t you
know that 76 percent of family caregivers say they don’t get
regular help from other family members? I thought you were the expert!
EAG: (sighs) OK, I guess you “win.”
Continue to do it all yourself without a break.
Take Time to Make Time
If you’ve decided you’re tired of “winning,”
and are ready to do what it takes to find other sources of help
and support, congratulations! You’re upholding the first principle
of caregiving, according to the NFCA: “Caregiving is a job
and respite is your earned right. Reward yourself with respite breaks
often.”
Respite is the term used to describe temporary care provided
to a person with disability or serious illness so the caregiver
can get a break. Respite can take place in or out of the home, for
any length of time, depending on available resources.
“We tend to find excuses as to why we neglect our social
life and stay home,” says Shirley Loflin, a caregiver to her
physically incapacitated husband and an advocate who works with
the Rosalynn Carter Institute of Caregiving in Americus, Ga. “As
much of a hassle as it is to get things lined up to leave, it can
be done; just begin early and make several lists.”
Do you have the most recent edition of "When a Loved
One Has ALS: A Caregiver's Guide"?
Get this comprehensive, book-length guide at your local
MDA office or see it in the Publications section of our site. One copy is free to each person with
ALS. Others can be purchased for $10 each.
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Loflin recommends letting your loved one participate in respite
preparation — the planning, lists, gathering of supplies —
“and they will feel a part of something fun instead of feeling
abandoned. I think my husband actually looks forward to my leaving
because it brings something different to his life, and that’s
always good.”
Some places to find respite help include:
