TARGETED RESEARCH, THOROUGH PATIENT CARE GOALS OF NEW ALS CENTER DIRECTOR

Hiroshi Mitsumoto, director of the MDA/ALS Center at Columbia Presbyterian Medical Center in New York, is a member of MDA's Medical Advisory Committee.

Neurologist Hiroshi Mitsumoto was born in Sapporo, Japan, in 1944. After completing medical school and advanced medical training in Japan, he came to the United States in 1972 and began medical studies here. After 16 years at the Cleveland Clinic Foundation in Ohio, where he headed an ALS center, he moved to the Neurological Institute of Columbia University in New York in August 1999. There he assumed the post of professor of neurology and director of the Eleanor and Lou Gehrig MDA/ALS Center.

Mitsumoto has co-authored three major books on ALS and dozens of articles and book chapters. One of his books, Amyotrophic Lateral Sclerosis, written with David Chad and Erik Pioro and published by Oxford University Press in 1997, is among the most respected references in the field.

Mitsumoto and his wife, Chizuko, who works in the art field, live in Sleepy Hollow, N.Y. They have two grown sons. The ALS Newsletter talked with Mitsumoto recently.

Q: How did you first become interested in ALS?

A: In 1973, soon after I came to the United States, I did a residency in neurology at University Hospitals of Cleveland. My mentor was Dr. Joseph Foley, probably one of the most respected American neurologists, a sort of grandfather of neurology. He made my life completely different.

After my residency, I wanted research experience, and I wrote to

Dr. Walter Bradley, who was then at Tufts in Boston [he's now director of the Kessenich Family MDA/ALS Center at the University of Miami].

He took me in and helped me obtain MDA support to study wobbler mice. Wobbler mice are a mouse model of motor neuron disease. In those days, we didn't have SOD1 mice [the most commonly used model today].

I really had the urge to do more clinical work, and the work in mice really increased my great interest in human ALS. I committed myself to taking care of patients with ALS and went to Case Western Reserve University in Cleveland, where I became faculty for the first time. I was assistant professor of neurology and neuropathology and wanted to develop an ALS center. But things didn't work out, and I ended up moving to Cleveland Clinic, which had a much larger patient population, and was building an ALS center there.

Q: There have been a lot of disappointments in ALS research. Where do we stand on this research today?

A: Things have not moved as fast as we wanted. I think we need more drugs. There's only riluzole now. Clearly, more efforts should be made.

Ten years ago, when ALS clinical trials started, everyone thought ALS would be the easiest disease to work on, because it has a fast, clear-cut progression. The end points are so clear. People thought this would be a disease we could deal with quickly and easily. It turns out that's not true. It's been very difficult.

Every single clinical trial we've done in the last 10 years has provided enormous new questions and new learning. But where we are now is still a very, very early stage of clinical trials. We have to face the fact that we're 20 years behind compared to cancer chemotherapy.

Without biotech companies, we could not do any clinical trials. But those companies needed short-term results and a profit. If the result was not promising, the drug was quickly withdrawn.

For instance, with CNTF [a neurotrophic factor that yielded a negative result when injected under the skin in ALS patients], you could be thinking about intrathecal [into the spinal fluid] injections. You could also think about using a viral vector [to deliver the gene for CNTF to cells]. You could try to develop a less toxic form of CNTF, or you might think about trying the drug at various stages of ALS.

Similar things could be applicable to GDNF.

I believe that neurotrophic factor research is in its infancy. It has to be investigated more. It's probably time that this research was taken up by academic investigators, who have different goals from biotech companies and can do different types of clinical research.

So far, BDNF is our last hope for neurotrophic factor research. I hope this turns out to be promising.

There are so many different processes leading to cell death. I think if we can tackle each step — deal with apoptosis [a natural "cell suicide" process that seems to be activated in ALS], glutamate transporters, free radicals, mitochondrial abnormalities — maybe we can handle this disease far better than we can now.

Even though we can't yet treat the final cause of this disease because we don't know the cause, let's treat every possible step in cell death that we know about.

Q: What about xaliproden, the drug Sanofi-Synthelabo is testing and which you have tested on patients in your practice?

A: It's said to be an oral neurotrophic factor enhancer. It's said to increase endogenous [inside the body] neurotrophic factors, particularly BDNF.

The company did two trials of xaliproden — one with riluzole, and the other with only xaliproden. They're not two completely separate trials; they're related. It's a very good design, a really ideal study.

They studied 800 patients without riluzole and 1,200 patients on riluzole, so they had 2,000 patients altogether.

As I understand the results, the survival data weren't strong enough, but there were many promising results with regard to pulmonary findings, functional scales and quality of life. It's very promising, but more work may be needed. I personally feel that the drug does something.

The investigators are blinded [don't know who is on the drug and who isn't] during the study, but I've seen no toxicity problems with this medication. It turns out to be safe, with no side effects that we can see. (See "Xaliproden," page 3.)

Q: What do you think about drugs that block glutamate? [Glutamate is a chemical that transmits signals in the nervous system and has been implicated in nerve cell death in ALS.]

I think we are dealing with something right with the glutamate theory. That's my opinion. But I don't know if this will give us a final answer.

Q: How about antioxidants?

A: My recommendation is, "Do no harm." As long as people use them in moderation, I have no problem. But some people spend so much time and money on these that I feel a little uncomfortable. We have no data, but I think moderation is indicated. Too much is probably harmful.

Some people use more of these drugs than they do food. They must have balanced food, good nutrition, and then an antioxidant dietary supplement is OK.

Unfortunately, there's a big gap between theory and practice. It's something like with neurotrophic factors. In theory, they work well. In practice, they don't work well in humans.

Q: What do you tell your ALS patients now?

A: I believe in aggressive treatment of symptoms. And I tell them to be positive, to hang in there until we find something better. I feel strongly that the more positive an attitude they have, the better the disease course. It's a very difficult thing to do, although easy to say, but that's what I think is important.

I believe in aggressive management of things like muscle cramps, drooling, respiratory problems, nutrition and communication. Our primary task is to improve the quality of life as much as we can.

There's a lot of malaise in neurologists, an attitude that "there's nothing we can do." This is very wrong. We should do as much as we can and not forget the quality of life of the patient and the caregiver. We need to pay serious attention to that area.

Yes, medication is important, research is important, but it doesn't seem to me that in six months or so we'll get an answer. Many patients are deteriorating in front of our eyes, and we have to take care of them as much as we can.  

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OLD ENEMY BECOMES NEW ALLY IN GENE THERAPY

Scientists at the University of Alabama at Birmingham have developed a new method of gene therapy that holds potential for treating ALS.

The scientists have designed a new viral vector (a virus engineered to carry a therapeutic gene) that specifically delivers its payload to motor neurons, the nerve cells whose death causes the progressive paralysis of ALS. The vector, they suggest, could be used to rescue dying motor neurons with genes that encode proteins such as neurotrophic factors (proteins that naturally stimulate the survival of neurons).

The team of scientists, led by microbiologist Casey Morrow originally anticipated that the new vector would be useful for treating spinal cord injuries. "But in any condition where you would have some form of neuronal injury, it might have some usefulness," said Morrow.

Ironically, the new vector is a disarmed version of poliovirus, a virus that attacks motor neurons so efficiently that it caused an epidemic of the paralyzing childhood illness polio in the 1950s, and was once seriously considered as a possible cause of ALS.

Like all viruses, once this lab-engineered poliovirus is inside a cell, it begins making copies of itself — viral minions that are supposed to burst the cell open and launch a second, larger attack. In Morrow's research, the virus has been reprogrammed so it can't make the outer armor that would allow its offspring to break free and invade other cells.

So, once it becomes trapped inside the cells it has attacked, this disarmed poliovirus — called a replicon — can only replicate its genetic payload, making copies of the therapeutic gene that it carries instead of copies of itself. "That's a critical safety feature of the system," said Morrow, explaining that disarming the virus makes it noninfectious.

Importantly, the poliovirus replicons created by Morrow and his colleagues retain their preference for motor neurons, so they can target a therapeutic gene specifically to the cells that are ravaged by ALS.

"The limitation of the system is that the expression [of the therapeutic gene] is for a short period of time, and then it disappears, " said Morrow. That's because our genes are made of DNA, while the poliovirus' genes are composed of RNA — the molecule that higher organisms use as a short-lived intermediate between DNA and protein. In animal cells, RNA from a poliovirus replicon can manufacture therapeutic protein for a while, but it eventually breaks down.

But Morrow is working on ways to overcome that problem. First, he and his group have shown that levels of replicon-derived protein remain high in mice given a series of replicon injections over time. Also, Morrow suspects that providing motor neurons with just a short-term supply of genes that produce neurotrophic factors could have long-term effects on their survival.

"What we're shooting for is a regimen that we could actually use to help restore neuron function, and then have the effect be permanent," said Morrow.

In the September issue of Nature Biotechnology, Morrow's group showed that their poliovirus replicons could deliver a protein called TNFa to the motor neurons of mice genetically modified to be susceptible to human poliovirus. Replicons carrying the gene for TNFa, which Morrow calls "a very nasty molecule in the central nervous system [the brain and spinal cord]", induced a short-lived neurological illness in the mice. Replicons carrying a sham gene had no effect on the mice, showing that the poliovirus itself didn't cause any harm.

Although their approach might seem counterproductive to therapy, it was just a first-pass test to see whether poliovirus replicons could deliver high enough levels of protein to have an effect on the nervous system. Now that Morrow and his colleagues have demonstrated that poliovirus replicons are up to that task, they're using the replicons to infuse the mice with potentially therapeutic proteins that might be beneficial to people with diseases like ALS. 

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FALL MEANS FLU SHOTS

MDA is offering free flu shots for people affected by any of the neuromuscular disorders covered by MDA's Program, including ALS.

Influenza is particularly hazardous for people living with muscle-wasting diseases, which can compromise muscles used in breathing. Flu shots help reduce the risk of respiratory infections.

People registered with MDA can get flu shots through their MDA clinics, or MDA will pay for a local doctor to give the shot. 

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SANOFI DRUG XALIPRODEN LOOKS PROMISING

According to information released in September by the France-based international pharmaceutical company Sanofi-Synthelabo, a preliminary analysis of two large clinical trials of xaliproden — previously known as "the Sanofi drug" or SR57746A — shows some promising results.

The compound was well tolerated and had positive effects on pulmonary function and measures of disease progression, the company said. "Favorable trends" with regard to survival time were noted. ("Survival time" was defined as time to "permanent assisted ventilation, tracheostomy or death.")

The term "favorable trends" implies the effect on survival didn't reach statistical significance, meaning the difference between the treated and untreated patients on this measure couldn't be distinguished from a chance occurrence with any certainty.

The results will undergo an in-depth analysis by investigators soon, according to the company's press release.

Sanofi-Synthelabo spokesman Jim Fusilli said further studies of the compound are likely.

The announcement didn't provide any data about measures of subjects' tolerance for the drug, pulmonary function, disease progression or survival time.

Xaliproden is thought to increase the body's production of neurotrophic factors, naturally occurring nervous system chemicals that have been shown to protect nerve cells under a variety of adverse conditions in laboratory experiments. The drug is given orally.

Sanofi-Synthelabo conducted two related, but semi-independent, trials of xaliproden beginning in 1997. More than a dozen MDA/ALS centers were part of the trials.

In one trial, xaliproden was given along with riluzole (Rilutek), the only ALS drug now on the U.S. market. In the other trial, no riluzole was given. About 2,000 patients in total were in the trials.

For more information, see the MDA Web site at www.mda.org and the Sanofi-Synthelabo Web site at www.sanofi-synthelabous.com. 

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TEAMING UP TO SHARE CAREGIVING

St. Louis Family Finds Small Miracles' in Network of Caregivers

When news of Jeff Hilliard's ALS diagnosis spread throughout his St. Louis community, friends responded with an outpouring of home-cooked meals, sympathy and offers of "what can we do to help?"

Jeff Hilliard with Abigail, Diana, Andrew and Danielle

Hilliard, 39, and his wife, Diana Wagner-Hilliard, knew they would need help as they coped with Jeff's rapidly progressing ALS symptoms. The pair, both attorneys, was already kept hopping with demanding careers and three children: Danielle, 7, Abigail, 5, and Andrew, 6 months.

Hilliard began experiencing ALS symptoms in June 1999, and the disease was diagnosed in May.

Wagner-Hilliard ultimately decided she needed to harness all the offers to help, and create some kind of system to organize the meals and donations that kept coming in.

Meanwhile, five women at the Hilliard's Queen of All Saints Parish formed a prayer group to ask for divine help in meeting the Hilliards' needs. But the women in the Catholic church wanted and offered to do more.

Wagner-Hilliard turned to the prayer group for help in organizing the deluge of kindness, and together the women created what's now known as JAG, or Jeff's Angel Group.

JAG consists of dozens of volunteers who take care of the mundane yet essential day-to-day tasks at the Hilliard home. The Hilliards also use MDA services and receive care at the MDA/ALS Center at Washington University in St. Louis.

JAG "captains" oversee dozens of volunteers in specific areas: grocery shopping, laundry, transportation, information gathering, lawn care, bill paying, house cleaning, baby-sitting and more. Fellow attorneys help fight insurance battles and work on other financial matters. There's even a group that's planning to build a room in the Hilliards' basement for out-of-town guests to stay in when they visit Jeff.

As his condition has progressed, the overall effort has become an amazing show of generosity and caring. Friends and even people who'd never met the Hilliards now assist the family.

When someone offers to help, Wagner-Hilliard or a captain graciously accepts, but also asks the person to fill out a form about specific forms of help.

"There were a lot of people coming up to her [Diana] saying can I help, can I help?" said Peggy Hart, a member of the prayer group and laundry captain. "Rather than just say sure, we could say, `Well, here are the areas we need help in. Which one sounds like your bag?'"

A WELL-OILED MACHINE

The system is designed to keep volunteers giving and doing no more than they're able, and doesn't heap too much on one person.

By having a concrete, scheduled duty or chore to help the Hilliards, friends who felt powerless are given an easy way to help.

"A lot of times people are willing to help, but they just need an idea, such as `Can you do two loads of laundry on Monday?'" Hart said.

Those involved with JAG say it has brought out the best in many people, and the effort has even garnered some local media attention. "The donations that have come in, including supplies, plumbing man hours [for the basement project] are just remarkable," Hart said.

JAG leaders looked to reference books such as Share the Care: How to Organize a Group to Care for Someone Who Is Seriously Ill by Cappy Caposella and Sheila Warnock.

Along with forms and charts to help volunteers organize such an effort, it has ideas, tips and strategies for group caregiving.

Hart said one key to JAG's success is a master list maintained by one volunteer who's the communication captain. The list details everybody who has helped or wants to volunteer, and what they would like to help with, Hart said.

"It's on the computer spreadsheet and it has what times are best for them, too," Hart said. Wagner-Hilliard knows if she needs something, she can just call a captain and it gets done. Captains meet weekly and frequently consult with Wagner-Hilliard to assess the family's changing needs.

Along the way, acquaintances have become close friends and other relationships have strengthened. The family has discovered invaluable "hidden talents" in friends, Wagner-Hilliard said.

For instance, friends with nursing backgrounds have been able to research equipment, and help give the Hilliards an idea of what Jeff's future medical and equipment needs could be. Currently, Hilliard uses a manual wheelchair for mobility. His speech is also affected by the disease.

KEEPING A `POSITIVE HOUSE'

Most of all, JAG has given the family quality time to be together, and a new source of energy as "fresh faces" appear to help each day.

"Jeff has frustrating days, Jeff has very sad days, but all in all his spirits are up. It's a very positive house, and that's what all these people help us do," Wagner-Hilliard said.

Wagner-Hilliard's advice to other families faced with ALS is simple: Accept help, and don't be afraid to delegate duties.

"Let people help you. They want to, they need to, and you need them to," Wagner-Hilliard said. "You're doing as much good for them as they're doing for you. You've got to let these people help because it's the only thing we can control."

Hart agreed, saying it's hard to compare anything to the satisfaction of helping someone in need, and it's a great feeling to know you've alleviated a burden, even if it's as simple as a trip to the grocery store.

"From our church standpoint, it's an opportunity to live out what we're talking and preaching about," she said.

Wagner-Hilliard can take comfort in knowing that the women in the original prayer group — and surely many others they've come to know — are still praying for her husband and family.

"They're praying for that big ol' miracle, and I have to keep reminding them that small miracles have happened by all these people coming out."

CAREGIVING RESOURCES

Books

Sharing the Care: How to Organize a Group to Care for Someone Who is Seriously Ill by Cappy Capossela and Sheila Warnock, 1995. Fireside, Simon and Schuster. $13.

The Resourceful Caregiver by the National Family Caregivers Association staff. A yellow pages of resources and information for caregivers. To order, call (800) 667-2968. $16.95.

Internet sites:

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KEEP FIGHTING, MDA

Editor's Note: The following message, sent to MDA National Chairman Jerry Lewis via MDA, expresses the urgency of the fight against ALS, as well as the invaluable help given by national MDA sponsors such as the International Association of Fire Fighters (IAFF).

Dear Jerry Lewis:

I know you receive thousands of letters annually, but please bear with me. I am a retired firefighter from Texas who has "filled the boot" many times for MDA.

I loved being part of such an honorable profession and loved seeing the IAFF president give you a check for millions of dollars each year, knowing I was a part of it. But now, I have an entirely different perspective.

In June of this year my wife (who is 49) was diagnosed with ALS. I have watched a woman who had never been sick in our 14 years of marriage, be ravaged by this disease in six short months. She experienced her first symptom in late February this year, and has already lost the use of legs, arms and hands. She was forced to quit her job in July, and we were forced to give up our home because of the loss of income.

In my career, I have fought fire inside buildings where I could not see; I have been caught and "run over" by fire in a wildland fire; and I have literally saved other people's lives. There is no way I can express the pain in watching the love of your life being attacked, and having no way to fight back. At the pace that this disease is progressing, I have very little time left with my wife.

The only solace I can find right now in this world is knowing that the efforts of my brother firefighters and MDA may someday prevent another family from experiencing this horribly emotional experience. My message to you is please continue the fight, because for those like me, it's the only fight we have. Dennis K. Haas Burnet, Texas

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NO MERIT TO PURPORTED BENEFITS OF SNAKE VENOM

There's been a recurring interest in using snake venom to treat ALS, but doctors and scientists insist the "treatment" is no more effective than taking a sugar pill.

The first reports touting the benefits of snake venom for ALS sprang up in the mid-1970s. Back then, relatively little was known about what causes ALS, and scientists noted a superficial similarity between ALS and polio, which is caused by a virus.

Before the advent of the polio vaccine, scientists showed that they could successfully treat polio with substances that stimulate the immune system — including snake venoms. So, in 1975, scientists in Boca Raton, Fla., attempted to treat a group of ALS patients with a cocktail of detoxified venoms from the cobra and krait snakes. Although the scientists thought they observed a beneficial effect, they failed to examine a "control" group of patients who didn't receive the cocktail.

Soon after, independent studies showed the effects of the snake venom mixture on ALS were no different from placebo, a neutral substance like water or the famous sugar pill given to members of a control group in a drug trial. There's now little doubt among scientists that the original study was flawed by the hopeful expectations of both the scientists and the patients.

Still, a Florida biotechnology company is reviving interest in snake venom treatment and marketing a new venom-based drug.

Will the new drug work?

"It is my suspicion that the current form of modified snake venom is no more effective than was its predecessor," said Walter G. Bradley, director of the Kessenich Family MDA/ALS Center at the University of Miami School of Medicine. Proof of the drug's effectiveness, Bradley explained, will require testing it in a controlled trial, similar in design to the studies that ultimately disproved the benefits of the first snake venom treatments.

The Florida company hasn't announced any immediate plans to test the effectiveness of the new drug against ALS. Until that happens, Bradley advised, "I do not recommend that patients try to get it."  

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JACK LEMMON, KATZ NAMED MDA VPs

An Academy Award-winning actor and a partner in a New York realty company have been named national vice presidents of MDA.

Jack Lemmon

Jack Lemmon of Beverly Hills and Sheldon C. Katz of Scottsdale, Ariz., and New York were both named to voluntary leadership positions with the Association.

Lemmon was featured on the 2000 Jerry Lewis MDA Telethon in a moving appeal about the importance of ALS research. The actor received an Emmy last month for his starring role in the TV movie "Tuesdays With Morrie" based on the best-selling book about a college professor with ALS, Morrie Schwartz.

Katz has been affected by ALS since 1982. He's a partner in the Katz Realty Group, which owns and manages apartment buildings in New York.  

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GENE THERAPY FOR ALS

Researchers at Johns Hopkins University in Baltimore and Thomas Jefferson University in Philadelphia are collaborating on a new idea — gene therapy for ALS.

Since the disorder is only rarely caused by a single, known gene, gene therapy may seem paradoxical. But, says Jeffrey Rothstein, co-director of the MDA/ALS Center at Johns Hopkins, this study seeks to use genes more as drug delivery systems than as replacements for faulty genes, as is done in genetic diseases.

The researchers are working on inserting genes for EAAT2, a protein that whisks glutamate away from the fluid surrounding cells in the brain and spinal cord. This protein, called a glutamate transporter, keeps glutamate from building up to toxic levels. Research shows that excess glutamate around neurons may be a key factor in cell death in ALS.

Meanwhile, a group in Switzerland has slowed the progress of ALS in mice by inserting genes for Bcl-2 into their spinal cords. Bcl-2 is a protein that has shown promise in preventing the death of neurons in laboratory experiments.

A group at Northwestern University in Chicago has used the gene for GDNF, another protein shown to protect neurons. This team put the gene into leg muscles of mice, where the protein made from the gene may have been "soaked up" by nerve endings near the muscle.

Rothstein remains committed to the pursuit of gene therapy for ALS, but says he'd rather use a drug, if possible, to get the same effect.

Gene therapy, he notes, especially of the central nervous system, is fraught with technical hurdles, and a drug would be much easier to get into the brain and spinal cord.  

In the brain and spinal cord, nerve cells send signals to other nerve cells via glutamate. Excess glutamate is then "sucked up" up by glutamate transporter molecules that sit on the surface of nearby glial (supporting) cells. It's then recycled for later use.

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MDA RESEARCHERS TRACKING DOWN NEW ALS GENE

MDA-funded scientists are on the verge of identifying another gene that causes ALS. The disease is traceable through families — and thus thought to have a genetic origin — in about 10 percent of all cases.

Of these cases of familial ALS (FALS), about 25 percent are caused by defects in the SOD1 gene. Other causes of FALS remain mysterious, but the researchers are homing in on a gene responsible for a rare type of FALS that occurs with a condition called frontotemporal dementia (FTD).

FTD — marked by socially inappropriate behavior, inability to carry out routine daily tasks and memory loss — is present in less than 5 percent of people with any type of ALS.

In five families who have FALS with FTD, the researchers discovered evidence for a defective gene somewhere within a small portion of chromosome 9. They didn't detect the defective gene in 15 families who have FALS without FTD.

The researchers included Teepu Siddique, co-director of the MDA clinic at Northwestern Memorial Hospital in Chicago; Robert H. Brown Jr., director of the MDA/ALS Center at Massachusetts General Hospital in Boston; Diane McKenna-Yasek (also at Massachusetts General Hospital); and Margaret Pericak-Vance at Duke University Medical Center in Durham, N.C. They published their findings in the Oct. 4 issue of the Journal of the American Medical Association.

The researchers suggest that — in addition to benefits for people affected by this rare form of ALS — identifying this new gene "may provide further insights into the pathogenesis of [ALS] and ultimately lead to new approaches to treatment."  

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HOLIDAY WISHES TIME

MDA is offering a collection of holiday cards, featuring six original works by artists who are affected by neuromuscular diseases. Proceeds from card sales benefit MDA.

The cards for the 2000 season feature winter and holiday scenes and, new this year, a Hanukkah theme. Artists range from a teen-ager to retired adults, using media ranging from watercolor paintings to digital creations.

Most of the artists featured on the cards have works in the MDA Art Collection. Cards are $16 for a box of 25, plus minimal shipping and handling charges.

To see a selection or to place an order, go to www.mda.org or call (800) 223-6011. Orders must be received by Dec. 4.  

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The Association welcomes gifts for ALS research honoring significant occasions of achievement. These gifts may be made in tribute to special people or to mark such events as anniversaries, birthdays, weddings, graduations or retirements.

THE ALS NEWSLETTER
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