Index to this Issue:

ALS RESEARCH — Where We’ve Been, Where We Are Now Some Thoughts as 2005 Approaches Holiday Stress Busters for Caregivers ALS Research Roundup Iron Overload Gene May Be ALS Risk Factor Celebrex Fails ALS Test Diaphragm Stimulation Study Open in Cleveland Humanitarian Finds Volunteering a ‘Good Life’ Toni Diamond, Wings Event Founder, Dies
	On the Cover: Neurologist Charles Thornton directs the MDA/ALS Center at the University of Rochester (N.Y.). His research has included studies of how aging affects muscle, and he’s particularly interested in bridging the gap between laboratory research and patient care.

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ALS RESEARCH — Where We’ve Been, Where We Are Now

by Margaret Wahl

Neurologist Alan Pestronk, who directs the MDA/ALS Center at Washington University in St. Louis, has conducted research on distinguishing ALS from disorders that resemble it.

For families affected by ALS, the wheels of research can’t turn fast enough. Results announced from laboratory studies take years to move to clinical trials, and clinical trials take years to conduct and analyze.

But to scientists, progress is moving at a dizzying pace. Only a little more than a decade ago, no one had any idea what caused ALS, and therapeutic trials were just stabs in the dark.

Then, in 1993, came the discovery by MDA-funded researchers that some patients with ALS (albeit a very small percentage) had mutations in a gene on chromosome 21 that carries the code for the enzyme superoxide dismutase 1, or SOD1.

Almost immediately, mice with this kind of mutation were bred, giving the ALS research community its first good model of human ALS, a prerequisite for screening treatments.

Although mice with SOD1 mutations aren’t an exact model of most cases of the human disease (which don’t result from SOD1 mutations), their symptoms and microscopic changes are so similar to human ALS that they’ve become the "gold standard" for research.

Superoxide dismutase is involved in detoxifying cellular compounds known as free radicals, byproducts of ordinary cellular metabolism that carry an electrical charge. They’re highly unstable, and, like their political namesakes, they tend to cause trouble, stealing parts of other cellular components.

Not surprisingly, the first hypothesis formed after the finding that ALS could be caused by SOD1 mutations was that the anti-free radical — or antioxidant — qualities of SOD1 were missing, leading to a buildup of free radicals in nerve cells and ultimately to their death.

That guess turned out to be wrong, because the SOD1 enzyme is in fact able to carry out its normal antioxidant functions in the face of most of the abnormalities that can affect it. At root, most SOD1 mutations appear to cause ALS by some other mechanism.

However, scientists learned along the way that free radical buildup, also known as oxidative stress, is nevertheless a major player in the death of muscle-controlling nerve cells (motor neurons) in all forms of ALS.

Antioxidants

After a small trial at Columbia University Medical Center in New York found that high doses of the antioxidant coenzyme Q10 are safe and well tolerated in ALS, a much larger, 19-center trial has been scheduled to start enrolling participants this month. (The study coordinator is Alexandra Barsdorf, at (212) 342-3026 or aib2104@columbia.edu.)

And the supplement creatine, which has antioxidant and other properties, is being studied in a multicenter MDA trial. (For information, contact Ruth King in North Carolina at (704) 355-8699 or ruth.king@carolinas.org.)

Neurotrophic Factors

As scientists studied the cells of ALS-affected mice and people, they found that a type of cell death known as apoptosis is common in the disease. This word, derived from Greek roots meaning "dropping from," follows a prescribed, orderly chain of events.

Like turning leaves, such cell death can be normal during certain phases of an organism’s development. But for mature nerve cells in the brain and spinal cord, which are replaced extremely slowly if at all, it’s a disaster.

Hoping to wage a successful battle against apoptosis, scientists set out in the late 1990s to test a group of substances that had previously been identified as neurotrophic, or "nerve-nourishing," factors, with the ability to protect cells from death despite various kinds of adversity. Within a few years, clinical trials of several neurotrophic factors were under way.

Unfortunately, so far, these compounds have failed to help people with ALS. Today, only one of them — IGF1, with the brand name Myotrophin — remains in clinical trials, although VEGF has shown promise in rodents.

After one large-scale clinical trial showed some benefit for IGF1 and another didn’t, the FDA required a third trial as a "tie-breaker." That multicenter MDA-funded trial should finish in the summer of 2007. (The study coordinator is Sherry Klingerman in Rochester, Minn., at (507) 284-0451 or klingerman.sherry@mayo.edu.)

Meanwhile, other investigators noted that an antibiotic called minocycline on the market to treat infections had protective effects on nerve cells. They found that minocycline can block a very early event in the cell death pathway — the release of a chemical called cytochrome c from inside the cell.

Minocycline, which also seems to have anti-inflammatory properties that may be beneficial, is now being tested in a large-scale MDA trial. (For information, contact Carolyn Doorish in New York at (212) 305-2027 or cd2141@columbia.edu.)

Stopping Glutamate

By 1995, it was clear from human trials in ALS that riluzole (Rilutek) had a modest benefit on survival in the disease.

Riluzole partially blocks the release of a natural substance called glutamate, which transmits signals between cells in the central nervous system. This "neurotransmitter" is necessary, but an overabundance of it is toxic, so it has to be cleared away from the receiving nerve cell quickly and recycled.

Later research showed that at least some people with ALS have defects in the clearance of glutamate from the area around nerve cells, which is normally accomplished by proteins known as glutamate transporters.

A key glutamate transporter in some ALS patients appears unable to carry out its mission, probably leaving excess glutamate to damage cells.

Still other research has shown that the "receptors," or landing sites, where glutamate docks on targeted nerve cells, are often abnormal in people with ALS. An error in production of a glutamate receptor seems to occur frequently in people with ALS, and it allows the receptor to admit more calcium into nerve cells than it should.

Although riluzole has modest benefits in ALS, researchers have surmised that there could be other drugs that might be even more effective at decreasing glutamate concentrations around nerve cells. Such a drug might be ceftriaxone, an antibiotic that, in studies conducted on cells and in mice with SOD1 mutations, showed that it could increase production of a glutamate transporter.

A trial of ceftriaxone is scheduled to begin in the early part of this year at more than 40 centers in the United States and Canada. (Watch this publication and our Web site at www.als-mda.org for information.)

Calming the Immune System

Decades of research have failed to show a clear attack by the immune system as a primary cause of ALS.

However, chemical indicators that the immune system is on high alert have been found in ALS, probably resulting from signals that cells are degenerating.

If this state is as harmful as many researchers believe it is, then anti-inflammatory drugs might prove helpful. Toward this end, the anti-inflammatory drug celecoxib (Celebrex), which had very promising effects on mice with ALS, was tried in people. Unfortunately, despite high hopes and good efforts, it failed to show benefit. (See "Celebrex Fails .")

However, the antibiotic minocycline, which is being tested in ALS, may prove to have inflammation-countering effects.

More Genes, More Pathways

Pediatric neurologist Philip Chance at the University of Washington in Seattle headed the team that recently identified the gene that causes a juvenile-onset form of ALS.

Although the vast majority of ALS cases probably aren’t genetic in origin, some 10 percent are thought to be clearly so, and genes may influence vulnerability to the disease.

Every time a new gene is found to play a role in ALS, understanding that gene’s functions gives scientists clues to pathways of motor neuron loss and preservation.

For instance, researchers have discovered that two genes — one called VAPB and another called alsin — can, when flawed, lead to ALS. The proteins made from each probably play a role in how substances are transported inside nerve cells.

And, this summer, researchers in Germany found that a third gene, for the dynactin protein, also involved in intracellular transport, could be an ALS risk factor.

This spring, MDA-supported researchers announced they had found the gene responsible for a juvenile-onset form of ALS. The normal function of the protein made from this chromosome 9 gene, now called senataxin, appears to be to prevent errors from creeping into genetic instructions as the cell reads them.

In September, the Hfe gene was implicated as a possible risk factor (see "Iron Overload Gene").

Each of these gene findings is likely to lead to future therapeutic targets in ALS.

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Some Thoughts as 2005 Approaches

by Christopher and Reda Rice

Chris Rice received an ALS diagnosis in 2001. The Houston couple serves as co-chairpersons of MDA’s ALS Division.

As the new year approaches, we want to share some of our feelings and thoughts about the past year and about our future. We hope that, if you have some of the same emotions, you’ll know you aren’t alone:

Grief: Unfortunately, we’ve had to watch others we’ve met and come to love pass on as ALS has taken their lives. We grieve for their families, spouses, children and friends. We pray for peace and joy to be with these loved ones as they continue on without that special person in their lives.

Admiration: We have exceeding admiration for the dedicated doctors and staff at MDA’s ALS center in Houston. They serve and help those of us with ALS and our families with positive attitudes and kind hearts. As we remember that they, too, lose friends to this disease but continue to strive for a cure and better treatments with dedicated hearts, our admiration grows. We thank them from the bottom of our hearts for the hope they’ve brought into our lives.

Peace: We experience peace as we trust in our Lord and a promise of a future in eternity that makes our time here on Earth just a fleeting moment. We find peace in the promises that we receive graciously — promises of a future with no diseases and no pain, promises that bring us all back together again.

Joy: Our three children bring joy to each day. They remind us of the beauty of the simple things as they play vigorously and laugh out loud. They enjoy each day and use an imagination that we envy. We watch them with hearts overflowing with love, as they ground us in what really matters — finding joy in all things.

Acceptance and Hope: These two feelings coincide in our lives. As we accept the changes that come with ALS, we don’t give up hope. We hold onto hope for a future that finds ways to slow the progression and hope for a future with a cure. Until that time comes, however, we willingly accept whatever obstacles come our way, knowing that God will use all these things for good.

A reflection on our emotions wouldn’t be complete without mentioning two biggies we try to avoid:

Fear: We know that fear for our future would only bring us worry and, consequently, destruction. We know we must put our trust in God and not live with concern or fear of things we might have to endure.

Complacency: Becoming complacent about our current condition would have an adverse effect on our hope. With complacency comes an acceptance of comfort and lethargy that could quench our spirits and dampen our hope. We never want to give up doing our part to help find a cure, no matter how small our efforts may seem in our minds.

As we look toward a new year, we get a renewed burst of energy and excitement in our hearts. We feel blessed to be part of MDA’s worthwhile effort and for its direct effect on our lives.

If you or someone you know is facing ALS, get involved in our future. With your holiday cards, remind family, friends, neighbors, co-workers and church families about MDA’s efforts. Volunteer to help with MDA events next year. You’ll be blessed beyond your imagination.

And most important… Never give up. 2005 could be the year!

 

ALS RESEARCH ROUNDUP

Iron Overload Gene May Be ALS Risk Factor

Two Hershey, Pa., researchers are part of a team that has uncovered what may be an important genetic risk factor for ALS.

James Connor

MDA grantee James Connor, a professor of neurosurgery at Pennsylvania State College of Medicine, and Zachary Simmons, professor of neurology at Penn State and director of the MDA clinic at Hershey Medical Center, found that a defect in a gene on chromosome 6 known as Hfe is a likely risk factor for ALS. Connor, Simmons and colleagues published their results online Sept. 18 in the Journal of the Neurological Sciences.

While defects in the Hfe gene have previously been associated with the iron overload disease hemochromatosis and with Alzheimer’s disease, this is the first connection made with ALS.

The protein normally made by the Hfe gene is thought to limit the uptake of iron by cells, to protect against oxidative stress and possibly to dampen inflammatory reactions. (Oxidative stress is a common form of cellular damage caused by electrically charged oxygen compounds, and is strongly associated with ALS.)

Zachary Simmons

Mutations in the Hfe gene are associated with increased cellular iron uptake, more oxidative stress and possibly with an altered inflammatory response.

The researchers studied 121 people with ALS and found that a particular mutation in the Hfe gene was more than twice as likely to occur in the ALS-affected group than in a control group. In the ALS group, 30.6 percent of the subjects carried the mutation, compared to 14.3 percent of those in the group without ALS.

The researchers then studied the effects of the Hfe mutation on nerve cells. They found it resulted in decreases in three proteins: beta-actin, which forms part of the cellular scaffolding; alpha-tubulin, which contributes to the formation of microtubules used for transport of substances in the cell; and superoxide dismutase 1, or SOD1, which is needed to detoxify molecules that contribute to oxidative stress. All these protein deficiencies are consistent with the types of changes in nerve cells that occur in ALS.

The authors say they don’t believe an Hfe mutation is sufficient to cause ALS by itself, but that it could be a contributing factor in disease causation in at least some cases.

They also say that “those patients with ALS who possess the Hfe mutation may differ from those without the mutation in their response to antioxidant therapy, and may respond to therapies that reduce iron intake or increase iron elimination.”

Celebrex Fails ALS Test

A one-year study of the anti-inflammatory medication celecoxib (Celebrex) in people with ALS has failed to show benefit, according to the Northeast ALS Consortium, which conducted the trial with support from MDA and Pfizer, makers of Celebrex.

The trial involved 300 people, two-thirds of whom received Celebrex and one-third of whom received a placebo (inactive substance), at 25 U.S. medical centers. Basing their hypothesis on laboratory studies of cells in culture and in mice with ALS, the researchers had hoped to demonstrate a slower rate of ALS progression with the drug.

“Celebrex worked in two laboratory models,” said MDA clinic director and research grantee Daniel Drachman, a neurologist at Johns Hopkins University Medical Center in Baltimore and a principal investigator on the Celebrex study. “There was more than enough reason to translate the research to humans, and it was a very well-done study.”

MDA Medical Advisory Committee member Merit Cudkowicz, a neurologist at Massachusetts General Hospital in Boston and a principal investigator and coordinator on the Celebrex study, said she’s committed to finding out why the drug didn’t work and to finding other therapies for ALS.

The consortium’s statement, released Oct. 25, says: “At 800 milligrams per day, Celebrex was safe and well tolerated. Celebrex did not have any demonstrated beneficial effects on ALS disease course. Studies are under way to assess whether Celebrex as used in this study had the predicted pharmacologic [drug-related] effects in the treated subjects. The study results will be presented at the International Motor Neuron Disease Association meeting on Dec. 3.”

Drachman said the challenge now is to see whether the failure of celecoxib in ALS was due to “an inherent flaw in the theory, or to a difference between mice and men, or to a dosage effect, or to lack of penetration of the drug into the nervous system.”

Diaphragm Stimulation Study Open in Cleveland

A small study of people with ALS who aren’t yet using ventilators but who are losing respiratory function is under way, and participants are still needed. The study’s purpose is to determine whether electrodes implanted into the diaphragm muscle and stimulated three to five times a day can maintain diaphragm muscle mass.

General surgeon Raymond Onders at University Hospitals of Cleveland says he’s implanted such electrodes into 14 people with spinal cord injuries, including the late Christopher Reeve, and that the strategy appears to be effective in that condition.

Onders, director of Minimally Invasive Surgery at University Hospitals and an associate professor of surgery at Case Western Reserve University in Cleveland, says the new system differs from an older procedure called phrenic nerve stimulation. In that technique, the nerve controlling the diaphragm was the target of the electrical impulses, which would be a problem in a disease of the nervous system like ALS.

In the approach being tested, the muscle is stimulated at the “motor point,” where the nerve comes into the muscle.

The year-long study requires nine visits to University Hospitals and will enroll 10 people with ALS who meet the inclusion criteria, for which there’s an extensive assessment and screening process. The initial goal is merely to maintain diaphragm muscle mass, but, Onders notes, his ultimate goal is to maintain patients’ respiratory function without a ventilator.

For information, contact nurse practitioner MaryJo Elmo at (216) 844-8594 or maryjo.elmo@uhhs.com.

Humanitarian Finds Volunteering a ‘Good Life’

Don Post throws the first pitch at a Kansas City T-Bones game on MDA Night.

For more than 20 years Don Post of Kansas City, Mo., has motivated others to volunteer for MDA and other nonprofit organizations. After receiving a diagnosis of ALS in 1989, he was determined to continue his lifelong mission of helping others in need.

“My volunteer work gives me a reason to get up every morning and allows me to feel productive,” said Post, who uses a manual wheelchair and motorized scooter. “It keeps me busy so I don’t have time to think about my situation.”

From cleaning and repairing homes and churches to helping with searches for people who’ve drowned in the Missouri River, Post, now 61, got his first taste of altruism at age 10 by volunteering with his Boy Scout troop. He went on to be a lifeguard at the community pool, teach Sunday School, speak on the issue of child abuse prevention, help out with a charity bike tour and volunteer at the Missouri Special Olympics as a “hugger,” congratulating each participant.

“I pretty much always made time to volunteer,” said Post, who also had a career in sales. “For me, it’s a way of life.”

A New Life, a Good Life

Difficulty with traveling and talking on the telephone led to Post’s retirement from sales work in 1987. Since then, he’s spent most of his time helping others. He refers to his post-ALS life as his “good life.”

“My disability has forced me to ‘stop and smell the roses,’” said Post, who enjoys visiting with friends, entertaining his grandchildren, cooking, writing upbeat poetry and working on a book about the recruitment, care and appreciation of volunteers. “I have discovered some truly beautiful, caring, giving people since my disability. Life is a wonderful place to spend time. The greatest things I have learned are patience and trust.”

Post has received several awards for his community service, including MDA’s Personal Achievement Award for Missouri.

Post held a part-time position as an event logistics and volunteer coordinator for his local Multiple Sclerosis Society chapter for 14 years.

Today, he coordinates volunteers on a nonpaid basis. Using a database of past volunteers, Post matches people with organizations seeking help. He then interviews prospective volunteers to make sure they’re given a task that they’ll enjoy.

“It’s just a matter of letting them know of a need and then following through to make sure they are treated properly,” said Post, who excels at making people feel appreciated. “I never ask anyone to help unless I’m there also to greet them and train them.”

Making a Difference

Post has helped out at his local Jerry Lewis MDA Labor Day Telethon since 1977. After losing the oldest of his four sons to a car accident in 1985, he tripled his efforts, maintaining that no parent should ever lose a child.

Post also attends most MDA Lock-Ups, helps with Harley-Davidson rides and is active with MDA’s local ALS support group.

He says his best memory from his work with MDA is “visiting MDA summer camp on VIP Day. I always leave there with a warm feeling about the ‘positive attitudes’ of the campers. I love a positive attitude.”

Toni Diamond, Wings Event Founder, Dies

Toni Diamond and Warren Schiffer at Wings in 2002.

Toni Diamond, founder of MDA’s Wings Over Wall Street gala, died on Nov. 11 after a four-year battle with ALS. She was 46.

Diamond, who lived in Southwick, Mass., enjoyed a 20-plus year career as a flight attendant with United Airlines before she received a diagnosis of ALS in 2000. She met her husband, Warren Schiffer, on a flight to Japan, and the couple often flew together in the ensuing years. Schiffer was constantly at his wife’s side throughout her ALS struggle, and was her primary caregiver.

Although her disease progressed rapidly, Diamond was known for not letting ALS dull her spirit. She and her husband decided to raise money for ALS research and funnel the proceeds to two MDA/ALS centers where Diamond had been seen — at Columbia University in New York and Johns Hopkins University in Baltimore.

In 2001, their efforts culminated in the first Wings Over Wall Street gala in New York — then called Wings of Hope.

Diamond attended the first Wings event despite having recently received a tracheostomy and a ventilator. By then she’d lost the ability to speak and all movement in her arms and legs. She received the event’s Spirit Award for her efforts in raising ALS awareness.

Diamond and Schiffer also attended the most recent Wings gala in late September. Since its inception, Wings Over Wall Street has raised more than $4 million for MDA’s ALS research program.

Diamond will be remembered by the Wings annual award named in her honor. The Diamond Award is given to a scientific leader dedicated to the eradication of ALS.

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