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| Your Source for the Latest Information About ALS |
Vol. 11, No. 7
August 2006 |
Index to this Issue:
Back to top
'Detox' Enzyme DNA Links Genes,
Environment, ALS
by Margaret Wahl
"When I saw the first set of data in March of last year, I
immediately sat up,” says neuroscientist Denise Figlewicz,
an MDA-supported ALS researcher at the University of Michigan in
Ann Arbor.
Figlewicz was looking at the results from a small study comparing
DNA from people with ALS and without ALS in Poland.
“This was a small sample size from a genetically isolated
population, and to get such a statistically significant effect is
a sign that you’re looking at something that’s real.
And a gene, or family of genes, already implicated in the Gulf War
syndrome is certainly the kind of candidate you pay attention to,”
Figlewicz says.
The something real, published online July 5 in Neurology, is an
association between particular variations in genes that carry instructions
for paraoxonase (PON) enzymes, and the development of sporadic ALS,
the type of ALS that isn’t clearly hereditary and affects
some 90 percent of those with the disease.
The three PON genes (PON1, 2 and 3), located along a stretch of
chromosome 7, carry instructions for enzymes that help metabolize
and detoxify a variety of man-made nervous system poisons, such
as pesticides, insect repellents, nerve gas and anti-nerve gas medications.
Figlewicz recognized what she had: the first example of how a person’s
genetic background can interact with environmental factors to produce
ALS.
Genes, Environment Long Suspected in ALS
It’s been known for decades that ALS can run in families,
but rarely. Only about 10 percent of ALS cases are clearly familial,
usually inherited in a dominant genetic pattern, and passed from
parent to child.
The question then became, could exposure
to a neurologic toxin, combined with genetically determined
impaired ability to metabolize it, be a perfect storm? |
But by the 1990s it was also becoming clear that some sort of genetic
predisposition, perhaps combined with an exposure to an environmental
toxin, virus or drug, was also a likely route to ALS.
By 2003, 12 years after the Gulf War conflict, surveys were showing
that veterans of that war were developing ALS at twice the expected
rate.
The question then became, could exposure to a neurologic toxin,
combined with genetically determined impaired ability to metabolize
it, be a perfect storm?
Gulf War Syndromes Linked to Low PON, High Toxins
|
Gulf War-related illnesses and studies
provided ALS researchers with clues.
|
Figlewicz says that she, like most ALS investigators, took the
early Gulf War data with a grain of salt.
“There are a lot of these studies where one person finds
an exposure to this or that, and probably they’re not wrong,
but nobody has been able to duplicate these,” she says. “In
Gulf War veterans, there were some positive studies, although they
were hard to pin down. There were environmental factors possibly
causing [various] neurological syndromes, not just ALS.”
It’s been hard to get funding to do this kind of epidemiologic
research into environmental exposures, Figlewicz says. “You
can say you’re citing previous literature as the reason for
your study, but [funding agencies] may say the previous literature
is garbage.” There have been reports based on “we have
a feeling there are more patients than usual,” she says, but
there are only a few investigators who’ve made an effort to
do serious statistical studies.
One such investigator is Robert Haley, a physician-epidemiologist
at the University of Texas Southwestern Medical Center in Dallas
and a specialist in Gulf War syndromes.
The Pentagon and the VA...had concluded
that this was due to stress, all psychological, a neurotic
problem. |
In the early ‘90s, soldiers returning from the Persian Gulf
began displaying various combinations of symptoms — impaired
thinking, lack of coordination, tingling and numbness in the extremities
and constant pain. (ALS, in those veterans in whom it developed,
wouldn’t become apparent until years later.)
“The Pentagon and the VA [Department of Veterans Affairs]
under Bill Clinton had a presidential advisory committee,”
Haley says, “and they had concluded that this was due to stress,
all psychological, a neurotic problem.”
But in 1997, Haley’s group published several papers showing
that exposures to organophosphate pesticides (such as that used
in flea collars, which many of the veterans wore to kill sand fleas),
the insect repellent DEET, nerve gas, and medication given to ward
off the effects of nerve gas were all correlated with the later
development of neurologic symptoms.
They described the symptoms as falling into three categories: Symptom
complex 1 they called “impaired cognition”; complex
2 they called “confusion-ataxia” (incoordination); and
complex 3 they described as “arthromyoneuropathy,” or
joint, muscle and nerve abnormalities.
In 1999, Haley, with co-workers at the University of Michigan,
published a study linking sluggish PON1 enzymes, as well as chemical
exposures, to these Gulf War syndromes.
The 1999 Haley study, Figlewicz says, was one of the few Gulf War
studies that looked at something specific. She considers it “probably
the most solid epidemiology of the studies related to Gulf War veterans.”
When blood samples were analyzed from 26 ill veterans and 20 who
described themselves as not ill, low levels of PON1 activity, and
the substitution of an arginine instead of a glutamine molecule
at a specific position in the enzyme, were found to be associated
with later development of neurologic symptoms.
The ill veterans also reported having been exposed to pesticides
or nerve gas, and having had severe adverse reactions to anti-nerve
gas medication.
Studies Showed Breakdowns Neurologic, Not 'Nervous'
“A lot of our man-made insecticides and herbicides are mimics
of natural organophosphates,” Figlewicz says. “The reason
they work is that they get into the body [of an insect] and do the
same things that the native compound would do, but when they attach
to an enzyme, they don’t come off.”
That enzyme they attach to is called acetylcholinesterase,
or AchE, and it’s responsible for the breakdown of
acetylcholine, a neurotransmitter that carries signals from nerves
to muscles in the voluntary nervous system and carries other signals
in the autonomic nervous system.
Organophosphates kill insects by latching onto AchE and preventing
it from breaking down acetylcholine. “The insect goes into
a tetanic [prolonged muscle contraction] state that is irreversible,”
Figlewicz says. “It keeps on getting stimulated with acetylcholine.”
Sarin nerve gas, to which military personnel were exposed during
the Gulf War when they exploded storage depots, acts similarly.
It too prolongs the effect of acetylcholine in the nervous system.
In anticipation of nerve gas exposures, military personnel were
given tablets containing pyridostigmine, an “antidote”
to sarin and related gases, but one with its own toxicity. In the
nervous system, pyridostigmine competes with sarin for a place on
the AchE enzyme. If it wins the competition, it substitutes its
less severe toxicity for the more deadly one from nerve gas.
“It’s pharmacologic musical chairs,” Haley says.
“If the pyridostigmine is on the cholinesterase, the sarin
can’t get on it.” Needless to say, if no nerve gas exposure
followed pyridostigmine ingestion, the soldier would experience
only the side effects, and no benefits, from the medication.
Meanwhile, the military, Haley says, was having a hard time believing
that neurologic symptoms seen after the war were anything other
than stress. “They said, ‘You’ve got two guys
serving right together, and one gets Gulf War syndrome, and the
other doesn’t. He just broke under stress.’”
Haley disagreed. “I knew from 10 years of research at the
Centers for Disease Control and a bunch of investigations that it’s
always shoe-leather epidemiology. Epidemiology comes up with plausible
theories, and then you’ve got to go to the lab and prove them.
Here we had a very plausible epidemiological association.
“I got on [the Internet database] Medline, and in about an
hour, I did a search. I think I searched on ’genetic polymorphisms,
enzymes and nerve gas,’ and there were two sets of literature
— a lot of enzyme studies and genetics about AchE variants,
and then a big literature on this other [enzyme] called PON. And
there was one name that was common to both literatures, and that
was Bert La Du, at the University of Michigan. I just cold-called
him and said, ‘Dr. La Du, this is Dr. Robert Haley. You don’t
know me, but I’ve been doing this study of Gulf War syndromes.’”
The collaboration between their two laboratories led to the identification
of PON1 activity and neurologic symptoms, published in the June
15, 1999, issue of Toxicology and Applied Pharmacology.
PON Gene Variants Found in Polish ALS Patients
Some time after the Gulf War data were published, Polish neurologist
Agnieszka Slowik, who was studying the possible role of PON genes
in susceptibility to strokes at Jagiellonian University in Krakow,
came to Denise Figlewicz’s lab in Ann Arbor for three months
of training in molecular genetics.
Together, and with knowledge of Haley’s data about Gulf War
neurologic syndromes, they decided to study Polish subjects with
and without ALS and examine their PON gene status. “The Polish
population is much more uniform than what you would get from a medical
center in the United States,” Figlewicz says. “People
leave there but haven’t been coming in. You can get statistically
significant results with a smaller number of people.”
A combination of the PON ...variants occurred 3.4 times
more often in ALS-affected subjects than it did in subjects
without the disease. |
Slowik, Figlewicz and others studied 185 people with sporadic ALS
and 437 healthy people as a control group and found that having
arginine rather than glutamine at position 192 in PON1 (the same
variant Haley’s group had found in the ill veterans) and cysteine
rather than serine at position 311 in PON2 were significantly associated
with having ALS.
A combination of the PON1 arginine and the PON2 cysteine variants
occurred 3.4 times more often in ALS-affected subjects than it did
in subjects without the disease.
As excited as Slowik and Figlewicz were about their data, which
they announced at the American Academy of Neurology meeting in April,
there’s one more step that scientists like to see completed
before they start taking their own work too seriously — confirmation
of the results by others, especially in different populations.
They got that, in the form of a U.S.-based study also presented
at the April AAN meeting and also published online July 5 in Neurology.
North American, Polish PON Variants Differ
Researchers in the laboratory of neuroscientist and neurologist
Teepu Siddique, at Northwestern University in Chicago, with colleagues
at Vanderbilt and Duke universities, found PON gene correlations
with ALS in a North American population, using a larger sample and
minimizing genetic differences with a different strategy from the
Figlewicz group.
Mohammad Saeed and colleagues in Siddique’s group, which
included neurologist Robert Sufit, director of the MDA clinic at
Northwestern, looked for possible variations in PON genes in sporadic
ALS patients versus a control sample.
Their findings differ somewhat from those of Figlewicz’s
group. Rather than detecting ALS-associated variations in the chemical
compositions of PON1 or PON2, or in their activity levels, they
found an association between developing ALS and having a variant
sequence of DNA between the PON2 and PON3 genes. (The disparity
between the two groups’ findings may be related to true differences
between the American and Polish ALS populations. Or, the particular
laboratory and statistical techniques each group applied may have
identified factors potentially relevant to both groups.)
Siddique’s team analyzed DNA from 1,891 North Americans with
and without ALS. In 450 of their cases, the genes of the ALS-affected
person were compared with those of his or her two unaffected parents
or one unaffected sibling, to minimize interference from genetic
background noise arising from ethnic differences.
“The [positive ALS association] signal is from the intergenic
region between PON2 and PON3,” Siddique said. “The biology
has yet to be clarified.” It isn’t, he said, from within
the PON1 gene.
ALS risk, Siddique’s team says in their paper, may in fact
be modulated by a PON cluster, rather than a single variant in a
single gene, at least in North Americans.
They also note that, because of the known function of PON enzymes,
these associations “hint towards a war-related environmental
exposure,” such as organophosphate pesticides and chemical
nerve agents, such as sarin, “in a genetically susceptible
host” as a possible causative factor in ALS.
None of Figlewicz’s subjects and probably a small number
(if any) of Siddique’s subjects served in the Gulf War, indicating
that PON variations may lower the threshold for ALS development
without the chemical exposures implicated so far, or that the Polish
and American subjects with ALS in these studies experienced some
of the identified chemical exposures, such as pesticides, outside
the Persian Gulf environment.
PON Gene Tests May Come Soon
Testing for PON gene variations isn’t yet widely available,
but Haley says his lab has developed a rapid test that has the potential
to be used on a large scale at an affordable price.
Right now, he says, such testing is available only through research
studies, costs about $2,000 and is time-consuming. He expects to
develop tests that can be performed “rapidly and cheaply.”
As a treatment strategy, his group has experimented with PON1 gene
therapy. They recently boosted PON activity in rats by giving them
genes for the glutamine type of PON1 and found “it has a pretty
phenomenal effect against acute cholinesterase [AchE] inhibition.”
Haley says he realizes gene therapy probably isn’t a solution
for most patients but that “it might be very useful to give
to troops before a battle.”
A toxin like sarin, he says, might be stored in fat cells and released
a little bit at a time, after which it would travel to the brain
and nervous system. “This is all fanciful,” he says,
“but if that were the case and you had high PON [activity],
you might mop it up before it got to your brain.”
As for other approaches, perhaps more practical and widely applicable
for people who find out they have high-risk PON gene types, Haley
says, “Can’t talk about it. But we’ve got some
other ideas.”
Back to top
Kessenich Golf Tourney Drives for
ALS
The first annual Mark F. Kessenich Jr. ALS Invitational Golf Tournament
was held June 12 at Deepdale Golf Club in Manhasset, N.Y., and was
highlighted by a live solo acoustic performance by platinum-selling
singer/songwriter Edwin McCain. The Kess ALS Cup raised over $225,000
to benefit the Kessenich Family MDA/ALS Center at the University
of Miami in Florida.
 |
|
(From left) Paul T. Kessenich, Mark F.
Kessenich III and Barbara Kessenich Robertson organized
the first annual Mark F. Kessenich Jr. ALS Invitational
Golf Tournament to honor their father, who died of ALS.
|
The tournament was organized by the late Mark Kessenich’s
three children — Barbara Kessenich Robertson of Greenville,
S.C., Mark F. Kessenich III of Garden City, N.Y., and Paul T. Kessenich,
of Manhasset, N.Y. In addition to raising funds for the Kessenich
Center, the children held the tournament to honor and celebrate
their father’s memory.
Mark F. Kessenich Jr. was a former Citibank and E.F. Hutton &
Co. executive, and CEO of Eastbridge Capital. He was also a scratch
golfer at the time he received a diagnosis of ALS in December 1994.
Kessenich died in 2001 at age 62. His sister, Joanne Knief, also
lost her battle with ALS in 2003.
With the support of Mark Kessenich Jr., his family and friends,
the Kessenich Family MDA/ALS Center was established in 1997. To
learn more about how you can help support the Kessenich Family MDA/ALS
Center, please contact Rebecca Rawson at (305) 243-6256.
And, for more information about MDA’s ALS Division, visit www.als-mda.org,
or call (800) 572-1717.
MDA Clinician, Researcher and Board
Member Awarded Endowed Chair
Neurologist and neuromuscular disease specialist Stanley Appel,
a long-time MDA research grantee and clinician, and a member of
MDA’s Board of Directors, has been named the recipient of
the Peggy and Gary Edwards Distinguished Endowed Chair for the Treatment
and Research of Amyotrophic Lateral Sclerosis.
Gary Edwards, a board member at Methodist Hospital in Houston,
where Appel practices, and his wife, Peggy Edwards, established
the $1 million endowed chair for a physician-scientist who champions
the research and treatment of patients with Lou Gehrig’s disease.
Gary’s mother, Jeannette, who died in 1985, had ALS and was
cared for by Appel and colleagues in the 1980s.
Appel is chairman of neurology and co-founder of the Methodist
Neurological Institute, where he’s also director of the MDA/ALS
Center and co-director of the MDA Neuromuscular Clinic.
Appel’s current research grant with MDA is for the study
of immunologic mechanisms in ALS.
“Mr. Edwards’ mother, Jeannette, was one of the beneficiaries
of our MDA clinical programs, and since those early days, we’ve
made significant progress. We truly appreciate the generosity of
the Edwards family and their encouragement of our ability to make
a difference in the lives of our courageous ALS patients,”
Appel said.
Robert Ross Will Be Missed, But Not Forgotten
On June 5, Robert Ross, MDA’s chief executive for 44
years, died at the age of 86, following complications of surgery
to repair a broken hip.
Under Ross’ guidance, MDA developed the most comprehensive
program of medical and community services of any voluntary
health agency in the country, including a network of 235 hospital-affiliated
clinics providing diagnosis and care for people with neuromuscular
diseases.
It was under Ross’ leadership that MDA recruited dozens
of business leaders and celebrities to help the Association;
established scientific and medical advisory committees consisting
of the best minds in the field of neuromuscular disease biology
and treatment; and developed what’s become the nation’s
largest and best known televised fund-raiser, the Jerry Lewis
MDA Labor Day Telethon.
Gerald C. Weinberg, Ross’ successor as MDA’s
chief executive, said, “Bob’s primary goal in
life was to bring about cures and treatments for neuromuscular
diseases. He knew and was excited that MDA was on the right
path for bringing that about.”
Although all the diseases in MDA’s program were vitally
important to Ross, ALS held a special place for him. During
MDA’s early years, in the 1950s and ‘60s, Eleanor
Gehrig, widow of famed Yankees baseball star Lou Gehrig, who
died of ALS in 1941, served as MDA’s national campaign
chairman.
Ross accompanied Eleanor as she traveled the country giving
speeches and interviews, and telling people like first lady
Mamie Eisenhower about the agency’s mission.
With Ross’ encouragement, Eleanor assisted with local
chapter development, recruited volunteers, including celebrities,
and persuaded radio and television program sponsors to give
free publicity to MDA’s annual fund-raising campaign.
She was an MDA corporate member from 1955 through 1964.
Eleanor Gehrig died in 1984, and that same year, MDA established
its ALS Division. By 1987, the Association had established
four MDA/ALS Centers, specialized clinics and research sites
dedicated to the multidisciplinary model of ALS care. Today,
there are 37 such centers across the United States.
Under Ross’ guidance, the ALS Division grew in strength
and scope, and funding for ALS research increased markedly.
His close relationships with influential people, such as Sen.
Jacob Javits and singer Dennis Day, both of whom had ALS,
and with actor Ed Fry, whose mother had the disease, helped
make the division what it is today.
In 1993, MDA-supported researchers, whose grants were awarded
through the scientific and medical advisory committees Ross
helped establish, identified the first gene that, when flawed,
can clearly cause ALS. Almost every laboratory study since
then has built on the finding that the superoxide dismutase
gene can set in motion a series of events that leads to the
death of nerve cells in the brain and spinal cord.
|
In 1956, Eleanor Gehrig assisted
MDA President William Mazer at the ground-breaking
ceremony for the Association’s Institute for
Muscular Disease in New York.
|
Two years later, Rilutek, the first drug to be approved by
the Food and Drug Administration specifically for the treatment
of ALS, became available. Its development rested in large
part on basic science research funded by MDA showing that
excess glutamate can poison nerve cells. Today, potentially
more potent compounds to remove excess glutamate, such as
ceftriaxone, are in the clinical testing pipeline.
The 1990s saw the identification of neurotrophic factors,
which provide needed support to nerve cells, and MDA’s
involvement in clinical trials to test several of them. MDA’s
first major involvement with the biotechnology industry, now
a cornerstone of its ALS research program, began in those
years.
By 1996, there was so much going on in ALS research and services
that it became necessary to launch a publication — The
MDA/ALS Newsletter, now the MDA/ALS Newsmagazine — devoted
solely to the disease.
Today, more than 30 active clinical trials and studies in
ALS are posted on MDA’s Web site at www.mda.org/research/ctrials.aspx.
Many of them are being conducted with MDA support or through
MDA’s centers and clinics.
Ross worked tirelessly on ALS research development right
up until the very week of his death. Recently, with his approval
and assistance, the Association established the ALS Translational
Research Advisory Committee (TRAC), whose purpose is to fast-track
promising research strategies and move them into clinical
trials.
Just this year, Ross appointed long-time health care services
coordinator Annie Kennedy, from the Washington, D.C., area,
to become director of MDA’s ALS Division, thereby helping
to ensure the smooth allocation of resources to the various
facets of MDA’s ALS program.
In his last months, Ross worked closely with Augie Nieto,
a fitness industry leader whose ALS was diagnosed in 2005,
on the launch of Augie’s Quest, adding millions of additional
dollars to MDA’s ALS-related efforts. (Nieto and his
wife, Lynne, are co-chairs of MDA’s ALS Division.)
Augie’s Quest has already funded an analysis of the
entire set of genes of 1,000 people with and 1,000 people
without ALS to determine what differences there are between
these groups. Following this fast-track effort, it’s
expected that experimental treatments based on these differences
can be developed.
To date, the Association has devoted nearly $190 million
to ALS research and services. For this year, MDA has budgeted
$7 million for ALS research and $10 million for services.
Ross will most certainly be missed, but his legacy will always
remain.
The MDA Robert Ross Memorial Fund has been established to
receive contributions in his memory. Gifts can be made through
the Web site at https://secure.mdausa.org/BobRoss/,
or sent to 3300 E. Sunrise Drive, Tucson, AZ 85718.
Back to top
All in the Attitude
Determining Your Quality of Life
From one to 10, 10 being the highest, how do you rate
your quality of life (QOL)? Before you answer that, you
have to figure out what the phrase “quality of life”
means to you.
Put Down Your Webster’s
 |
|
Darlene Bates and granddaughter
Noah Boston
|
Patricia O’Connor, the nurse case manager for the
Forbes Norris MDA/ALS Research Center at California Pacific
Medical Center in San Francisco, defines QOL as the meaning
and satisfaction that an individual derives from his or
her life.
“I’ve seen many, many patients who would
all define the quality of their life to be exceedingly
different from each other,” says O’Connor,
who’s been at the ALS center for nine years.
Found to have ALS in November 2001, Darlene Bates uses
a power wheelchair with a head control device and an augmentative
communication device, and says that having a high QOL
means being able to enjoy her grandchildren and playing
computer games, which she can do by using a head control
mount.
Bates, 58, divides her time between Edmond, Okla., and
Unionville, Va., staying with her two daughters and their
families.
Edmond Sistek of Pikesville, Md., who was found to have
ALS in June 2003, says that living with his partner of
10 years, Harriet Rosenthal, makes his QOL skyrocket.
Sistek, 69, who walks with a cane for balance and has
limited arm, hand and shoulder strength, retired at age
62 from teaching math and driver’s ed to at-risk
youths.
Other things that add to his quality of life are babysitting
his two grandsons and going to their soccer games. Sistek
also enjoys going to the horsetrack every week.
“There’s nothing a gambler enjoys more than
the hope that he’s going to win,” Sistek says.
“Every day that I go to the racetrack, I enjoy eight
races. I know for a fact I’m not going to win all
eight, but the fact that I may win three or four is what
makes me go back.”
The Eye of the Beholder
Often when QOL studies are conducted, the main concern
is what physical capabilities you possess, says O’Connor.
For example, if you can’t eat independently, the
studies score you low on that account. You get another
low score for not being able to walk.
“The scores can look like people have an awful
QOL. Well, anyone who has been working in the ALS community
knows that that is poppycock. The people MDA studies do
not define themselves by their physical abilities,”
she says. “Other studies, including MDA studies,
have shown over and over that even people who are extremely
disabled can see themselves as having an excellent QOL.”
John Sandner, who received a diagnosis of ALS in March
2001 and uses a power wheelchair with a sip-and-puff device,
lives with his wife, Cheryl, in McFarland, Wis. With the
help of a friend, Howard Davis, who has quadriplegia due
to a diving accident, Sandner, 59, realized early on that
he had more control over his life than he originally thought
after his diagnosis.
|
John and Cheryl Sandner (center)
and friends (including a bust of Nelson Mandela)
|
“When this disease started, Howard said to me,
‘Think of the things you can do, John, not the things
you can’t do,’” Sandner says. “Whenever
those thoughts about, ‘Hey, I’d really like
to go bicycling or canoeing or playing basketball’
start to depress me because I can’t do that, I think
about the things I can do, which is talk to my friends
and enjoy time with my family.”
Having 11 grandchildren makes for an adventurous lifestyle
for Sandner.
Cheryl reveals that Sandner’s sense of humor and
positive attitude help improve his QOL, and that friends
are always over because he’s so much fun to be around.
Loss of independence has a huge impact on QOL, and that’s
something people rarely have control over. Finding ways
to do as much for yourself as possible can help you to
keep your QOL intact.
Bates was extremely frustrated when she had to wait for
someone to push her manual wheelchair, but with her head
control device and power chair, she can go where she wants,
whenever she wants and at the speed she desires.
Change in Definition
“What I’ve seen of people with ALS who have
a deterioration of their physical abilities over time
is that what is important at one point in their illness
is less important at another time,” O’Connor
says. “Early on in the disease process, work may
be very important and doing a good job helps to define
QOL. Later on, work will define a person less, give less
satisfaction, but their family may become most important.”
When Sandner retired from teaching business management
at Upper Iowa University in Fayette in 1998, he and Cheryl
became involved with their MDA/ALS support group, helping
their “community” by sharing their experiences
and tips for living with the disease.
Sandner says that having a purpose makes his QOL much
higher. The couple recently spoke to a group of sixth-grade
students about living with ALS.
“The hardest thing to witness is someone who is
less strong than she once was but continues to define
her QOL by her ability to ski,” says O’Connor.
“She can be miserable because she’s unable
to ski, but in my experience, eventually almost everyone
begins to have different priorities over time.”
ALS RESEARCH ROUNDUP
by Margaret Wahl
Mouse Stem Cells Treat Paralysis
in Rats
 |
|
Normally, glutamate flows across a cleft from one nerve cell to another and is then quickly removed from the area by glutamate transporters. Rothstein's research suggests glutamate transport is deficient in ALS and that ceftriaxone improves it.
|
Researchers at Johns Hopkins University in Baltimore and SUNY Upstate
Medical University in Syracuse, N.Y., have developed a multistep regimen
that they say improves the functional effect of transplanted stem
cells in paralyzed rats.
The research team, led by MDA grantee Douglas Kerr at Hopkins and
including Jeffrey Rothstein, who has MDA research funding and directs
the MDA/ALS Center at the same institution, say their strategy restored
functional nerve-to-muscle connections and movement in the back legs
of rats that had been paralyzed by a virus.
In a four-step process, the investigators transplanted mouse embryonic
stem cells and injected the nerve growth factor GDNF into the sciatic
nerve near the spinal cord, and at the same time, infused two compounds
that counteract the effects of myelin, a normal substance that ensheathes
nerve fibers but which has been found to interfere with the growth
of new fibers.
The cellular environment is “hostile” in ALS, Kerr said,
because of inflammation. “Cells would have to be given with
inhibitors of this destructive inflammation,” he said, “but
I think as we learn more about the specifics, we’ll be better
able to transplant cells effectively and protect them from the ravages
of the local environment.”
Nevertheless, the authors say in their paper, published online June
26 in Annals of Neurology, the research demonstrates that “restoration
of functional motor units [a nerve cell with fibers connecting to
muscle fibers] by embryonic stem cells is possible and represents
a potential therapeutic strategy for patients with paralysis.”
Ceftriaxone Trial Opens at Eight
Centers
A study of ceftriaxone, an antibiotic approved by the Food and Drug
Administration to treat certain infections, is now under way at eight
U.S. centers, under the direction of neurologist Merit Cudkowicz at
Massachusetts General Hospital in Boston.
If safety, tolerability and drug metabolism data obtained on 60 subjects
early in the study are favorable, the investigators plan to enroll
a total of 600 participants at 40 centers to determine ceftriaxone’s
effect on survival.
The study is funded by the National Institutes of Health, but its
scientific basis stems largely from MDA-funded research conducted
by neuroscientist Jeffrey Rothstein at Johns Hopkins University in
Baltimore.
Laboratory studies have suggested that ceftriaxone improves the removal
of the potentially toxic nervous system chemical glutamate from the
vicinity of the nerve cells that degenerate in ALS.
For more information, see www.mda.org/research/view_ctrial.aspx?id=164,
or contact Fran Murphy at Massachusetts General Hospital, at (617)
643-3980 or fmurphy@partners.org.
Lipitor Being Tested in Houston
The cholesterol-lowering drug Lipitor (atorvastatin), which appears
to modify the inflammatory process, is being studied at the MDA/ALS
Center at Methodist Neurological Institute (MNI) in Houston to see
whether it can alter the course of ALS.
Inflammation, a process controlled by the immune system, is suspected
of playing a role in ALS. “We, along with many other scientists,
feel that the immune system is activated in ALS,” said neurologist
Ericka Simpson, who co-directs the MDA neuromuscular clinic at MNI
and is the principal investigator on the Lipitor study.
Simpson said the release of pro-inflammatory molecules in the brain
is associated with nerve cell injury and dysfunction but that “the
immune system has the capability of being reparative under the right
conditions. Statins such as Lipitor may switch the injurious role
of the immune inflammatory response in ALS to a reparative one.”
The 50-person, one-year study, with funding from Pfizer Pharmaceuticals,
makers of Lipitor, will compare the drug to a placebo (inert, look-alike
substance).
For information, see www.mda.org/research/view_ctrial.aspx?id=165,
or contact Peggy Allred at MNI at (713) 441-5191 or pallred@tmh.tmc.edu.
Investigators Testing Variant of Parkinson’s
Drug
Investigators at the University of Virginia in Charlottesville are
testing a compound known as R(+) pramipexole in people with ALS, to
see whether it alters their decline in function or changes biochemical
markers of the cell-damaging process known as oxidative stress.
James Bennett, a professor of neurology at the University of Virginia
School of Medicine, became interested in testing R(+) pramipexole
in ALS a few years ago, after S(-) pramipexole, whose structure is
a mirror image of the R form, was found effective in treating Parkinson’s
disease.
S(-) pramipexole was developed into the drug Mirapex, which mimics
the brain chemical dopamine and acts as an antioxidant, combating
oxidative stress. It enters the nervous system and the mitochondria,
the sites of energy generation inside cells.
Bennett, a physician who has a doctoral degree in pharmacology, recently
found that 15 ALS patients tolerated 30 milligrams a day of R(+) pramipexole,
which does everything the S(-) form does except mimic dopamine, which
isn’t a goal in ALS treatment.
Thirty milligrams is about five times the tolerable dose of the S
form, says Bennett, who’s now testing one ALS patient at a time
to see how high he can boost the dose of the R form.
The investigators aren’t seeking new trial participants at
this time, but they may be in the future. “So far the results
are encouraging for slowing disease progression,” Bennett says,
“but there aren’t enough data yet to draw any firm conclusions.”
Back to top
Hitting the Road With Bill Wilcoxson
by Kathy Wechsler
For Bill Wilcoxson and his wife, Joanna, of Pasco, Wash., a diagnosis
of ALS in May 2004 led to a new adventure — a chance to travel
the country and visit its historical sites — on the open road.
Ready for Takeoff
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Bill and Joanna Wilcoxson use their RV
to explore.
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Shortly after his diagnosis, the Wilcoxsons retired from their
jobs, sold their house and 14 acres, and purchased a 40-foot RV
so that they’d be able to spend as much time as possible with
each other while taking off on an adventure once a month. They tow
their SUV behind for side trips.
“We talked it over and said, ‘Hey, we’ve got
things we’ve gotta go see,’” says Wilcoxson, 65,
who’s MDA’s 2006 Personal Achievement Award recipient
for Washington. “We decided we would go see some of the things
that we haven’t seen and do some of the things that we want
to do before I pass away.”
The open road has taken them across the country to such breathtaking
places as the Grand Canyon, Mount Rushmore and Yellowstone National
Park, home of the Old Faithful geyser.
“There’s a fort that was built during the Second World
War on the mouth of the Columbia River,” Wilcoxson says. “A
lot of people don’t even know that it’s there —
we found it by accident one time.”
The couple has explored a ghost town and an old mining town in
the mountains of Arizona. From fishing with their grandchildren
in eastern Idaho to enjoying a relaxing stay in an RV resort on
the Washington coast, Wilcoxson and his wife know how to keep things
interesting.
“We don’t really make hard-core plans per se, like
a lot of people do, because if we see something that we like, we
might stay for a week instead of just a day or two,” says
Wilcoxson.
Between travels, Wilcoxson, Joanna and their Australian shepherd
mix named Sassy park the white and tan RV that they call home at
Sandy Heights RV Resort. From there, Wilcoxson enjoys going to his
grandchildren’s sporting events and playing poker with friends
at a small casino.
The Tank is Half Full
Wilcoxson, who had worked as an electrician and welder for 40 years,
began to realize that something was wrong when he failed his annual
welding test because he couldn’t keep his arms up.
Being a volunteer fire fighter and EMT for 15 years has made an
impact on the way he feels about having ALS, says Wilcoxson, who’s
ambulatory with leg braces and sometimes uses a cane. He has a lightweight
power wheelchair that he uses for long distances.
“When I’d be in a situation when someone was in a serious
way, I’d try to give them the positive outlook of their situation,”
he says. “Trying to help other people be positive has brought
on a positive attitude of my own.”
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The Wilcoxsons' son-in-law and daughter, Jeff and Tracy Lascheid, and grandchildren Erin, Alex and Monica
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Wilcoxson hasn’t had to make many adaptations to the RV —
only a ramp placed on the outside steps to walk up for easy access
— but he’s handed over some of the RV maintenance to
Joanna. He still can drive the vehicle.
Because of the ALS progression, the couple has decided that the
coming winter will be their last in the RV. That doesn’t mean
their traveling is over. New York and the Smithsonian Institution
in Washington are on the agenda for the future.
On the Road Again
A longtime friend of MDA, Wilcoxson has always watched the Jerry
Lewis Telethon every Labor Day weekend and donated to “Jerry’s
kids” — way before he found out that he’d one
day need the Association’s help.
“MDA has helped me by easing my concerns and has kind of
helped me slow the process down by not worrying about it,”
he says. “They’ve put me in touch with a lot of people
in my same situation.
“I just can’t say enough about the people that are
involved with MDA — they’re so friendly. They’re
people who are concerned about people. Just that alone, knowing
somebody out there cares about me really makes a difference.”
The couple is involved with the local Telethon in Kennewick and
was profiled and interviewed from their RV on last year’s
local broadcast. This year, they attended the Harley-Davidson Gala
in Spokane.
Wilcoxson spends much of his free time working with MDA’s
Spokane Health Care Service Coordinator Syd Pifer to develop fund-raising
ideas for the Tri-cities (Richland, Pasco, Kennewick) area. He hopes
to participate in the Tri-cities’ very own Harley-Davidson
Gala and the Walk for MDA, both taking place in October.
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