Enrollment Open for Three New ALS Clinical Trials

So far, efforts to find an effective drug treatment for ALS (amyotrophic lateral sclerosis) have led only to riluzole, which slows the disease down by just a few months.

But ALS researchers are taking a more aggressive tack than ever, and MDA-funded scientists are launching clinical trials of three drugs traditionally used for other diseases — the arthritis drug Celebrex, the breast cancer drug tamoxifen and the antibiotic minocycline.

Celebrex

Daniel Drachman and Jeffrey Rothstein, co-directors of the MDA/ALS Center at Johns Hopkins University in Baltimore, began probing Celebrex as a possible ALS treatment more than two years ago.

Celebrex (celecoxib) was originally developed to reduce the inflammation that causes arthritis, and it works by inhibiting COX-2 — an enzyme in the body that manufactures pro-inflammatory hormones called prostaglandins. It turns out that overactive COX-2 has many consequences — including inflammation, production of free radicals and toxic blasts of the brain chemical glutamate — all of which are thought to contribute to the destruction of muscle-controlling nerve cells (motor neurons) in ALS.

Rothstein and Drachman put these clues together and began testing Celebrex in laboratory models of ALS. Last year, in a groundbreaking study, they showed that a Celebrex-like compound could protect isolated motor neurons from a toxic exposure to glutamate.

Last month at the annual meeting of the Society for Neuroscience, they reported that, in mice with a mutant version of the SOD1 gene that causes familial ALS, Celebrex delayed disease onset by 54 days and prolonged survival by four weeks.

"We've now tested [Celebrex] in two models of ALS that are quite different, and in both cases, it worked. So, we're optimistic about its potential for helping people with the disease," Drachman said.

A clinical trial of Celebrex, led by Drachman, Rothstein and Merit Cudkowicz of Massachusetts General Hospital in Boston, is now open for enrollment and is seeking 300 participants. The MDA-funded trial will take place at 25 centers across the country, most of which belong to a group known as the Northeast ALS Consortium.

It's expected that the trial will last about two years, with one year open for enrollment, and a one-year study period for each participant. By random assignment, 200 participants will receive Celebrex (provided by pharmaceutical giant Pharmacia) and 100 will get a placebo. After the one-year study period, all participants will be offered Celebrex for the duration of the trial.

For more information, contact Cudkowicz's assistant Fran Murphy at (617) 726-9122 or fmurphy@partners.org.

Tamoxifen

Benjamin Brooks, director of the MDA/ALS Clinical Research Center at the University of Wisconsin in Madison, happened upon tamoxifen's promise for ALS when he began treating a patient who developed ALS and breast cancer almost simultaneously.

Over several months, while the woman was receiving tamoxifen for her breast cancer, Brooks noticed that her ALS was taking an extremely slow course. She showed little decline in muscle strength for more than four years.

Tamoxifen (Nolvadex) targets breast cancer by inhibiting the female hormone estrogen, but Brooks believes its potential for fighting ALS may lie in its effects on protein kinase C (PKC), an enzyme involved in cell growth and gene regulation. Work by other scientists has shown that PKC activity is unusually high in the spinal cords of people with ALS, he said.

At the neuroscience meeting, Brooks reported that he's tested tamoxifen in mice with an ALS-like disease caused by a virus. At an optimal dose, the drug delayed disease onset by seven to 12 days and prolonged survival by eight to 17 days in the treated mice. Male and female mice had equivalent responses to the drug, suggesting that it could work effectively in both men and women with ALS.

With support from MDA, Brooks and his colleagues have begun enrollment for a year-long clinical trial of tamoxifen in 80 people with ALS. Participants will be divided into four groups of 20, each of which will receive a distinct dose of the drug, ranging from low to high.

For more information, send e-mail to alscrc@neurology.wisc.edu.

Minocycline

Minocycline (Minocin) is used to treat infectious diseases, but Paul Gordon, director of the MDA/ALS Center at the University of New Mexico Health Sciences Center in Albuquerque, believes it might hold promise for treating ALS.

In addition to its antibiotic effects, minocycline appears to block the action of caspases — enzymes that trigger cells to die. Caspases help eliminate excess neurons in the developing brain, but there's evidence that they run amok in ALS and other neurological diseases, destroying neurons in the adult brain.

Last year, Robert Friedlander of Brigham and Women's Hospital and Harvard Medical School in Boston found encouraging evidence that caspase-blocking drugs might be able to stave off ALS and Huntington's disease. In an MDA-funded study, he showed that a caspase inhibitor called zVAD-fmk prolonged survival in mice with ALS, and in another study he showed that minocycline had a similar effect on mice with Huntington's.

Gordon is proceeding with clinical trials of minocycline because, unlike zVAD-fmk, it's already used in clinical settings, and it can penetrate the brain and spinal cord when taken orally.

A pilot trial of 20 participants is currently under way and still open for enrollment, and a larger trial is already being planned.

For more information, contact trials coordinator Martha Meister at (505) 272-3194.

Information about all three trials can be found on MDA's Web site at www.mda.org/research/ctrials.aspx.

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Gulf War Vets Have Higher ALS Risk

A new government-funded study has shown that soldiers who served in the Gulf War were nearly twice as likely to develop ALS as other military personnel. Study co-author Hiroshi Mitsumoto said the findings should encourage researchers to investigate possible environmental causes of ALS.

"We need to work with topnotch epidemiologists to find any environmental factors, but I don't think we can conclude that some military factor is the key," said Mitsumoto, who co-directs the Eleanor and Lou Gehrig MDA/ALS Center at Columbia Presbyterian Medical Center in New York.

The study examined nearly 700,000 U.S. military personnel who were deployed between Aug. 2, 1990, and July 31, 1991, in the Persian Gulf War against Iraq.

Of those veterans, 40 developed ALS — roughly twice the ALS risk found among 1.8 million veterans who weren't deployed to the Gulf region during the same period.

Mitsumoto said the results reveal a statistically significant difference between the two groups, but the biological significance isn't clear.

"It's certainly not a big, big difference. What I'm worried about is that the war was over almost 10 years ago, and we may have missed the opportunity to find a potential cause [for the difference]," he said.

Based on the results, the government is likely to provide compensation for Gulf War veterans who developed ALS, officials from the Veterans Administration said. See The ALS Newsletter, vol. 5, no. 2.

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People With ALS Win With Multidisciplinary Team Approach

(From left) Respiratory therapist Marilyn Graham, speech-language pathologist Pamela Mathy and physical therapist Deborah Taylor wait while Kumaraswamy Sivakumar, director of the MDA/ALS Neuromuscular Research Center in Phoenix, examines Rita Yorke.

Every Thursday morning at 8:30, six or more health care professionals squeeze around a small table in a corner conference room at the MDA/ALS Neuromuscular Research Center in Phoenix. Since their patients will begin to arrive at 9 a.m., this half-hour promises to be the quietest part of an otherwise hectic day.

On the table is a pile of manila file folders — some thin and shiny, others frayed around the edges and thick enough to resemble telephone directories.

This meeting reveals the essence of MDA's multidisciplinary team approach to treating ALS — one followed at each of the Association's 25 ALS research and clinical centers across the country.

Not 'Just' Patients, But People

Speech therapist Pamela Mathy (right) evaluates Rita Yorke while intern Meri Bickell observes.

The MDA/ALS Center in Phoenix, located at St. Joseph's Hospital, is home to approximately 160 manila folders, each representing a resident of central or northern Arizona who has ALS.

But to center director Kumaraswamy Sivakumar and his team, each folder represents much more than just another medical chart. It represents a human being — often frightened, usually with a family — who faces both an uncertain future and a life-or-death battle against an unbeaten opponent.

"This is a group of patients whose disease does not get better, and they are left with enormous physical, psychological and social difficulties," Sivakumar, a neurologist, explains. "And there is an enormous amount of stress at home because of the fact that this is a fatal illness."

Concerns about stress are as much a driving force behind Sivakumar's team approach to treating ALS as are the medical and scientific benefits.

"I give the prognosis in a staged fashion," Sivakumar says. "I do not say that it is a fatal illness in the first visit." Sivakumar also notes that ALS progresses at different speeds for different people, making it impossible to make an accurate prognosis until well after that first visit.

Pamela Mathy, a clinical professor of speech and language pathology at nearby Arizona State University in Tempe, is the speech and language pathologist on Sivakumar's team. Mathy explains, "Some patients approach a diagnosis of ALS by demanding all of the information available, while others need to be introduced to the prognosis more carefully."

Mathy says that, when she assesses the status of someone's respiratory and swallowing functions, "sometimes the patients actually resent my being there, because they don't feel they're having problems in these areas yet. Over the years I've learned not to take that personally. I have to just be here when the patient is ready to need me."

The Starting Lineup

Dietitian Irene Hovey is an important team member.

At the Phoenix center, patients are seen every three months to have their progress measured by each member of Sivakumar's team.

To make this work smoothly, the Phoenix team uses a system of color-coded lights mounted on a panel outside each examination room. Each position on the team is assigned a color, and each light switch has three positions: off, on and blinking. A blinking red light, for example, means the patient is ready to be seen by Dr. Sivakumar. If the red light is on steadily, Sivakumar is in the room and shouldn't be disturbed. And if the red light is off, then Sivakumar has probably already been there and gone.

Blue lights signal speech and swallowing therapists; yellow lights are for respiratory therapists; white lights indicate physical and occupational therapists; green lights are for research fellows, hospital residents and genetics counselors; and the clear lights belong to the team's social worker.

Besides regular team members, the center can refer patients to specialists at St. Joseph's, such as a pulmonologist, cardiologist or gastroenterologist, if their expertise is needed for management of the person's ALS.

Documentation and Communication

During each visit, team members enter their findings using flow sheets designed by Sivakumar. Each flow sheet documents up to six clinic visits, allowing each team member to see at a glance the progression of the disease in a given person.

"Based on that flow sheet we can decide on what interventions are necessary and what issues have been discussed with the patient," Sivakumar explains.

The flow sheet uses the standardized ALS Functional Rating Scale, with ratings from 0 to 4, designed to save time and paperwork while allowing the center to feed accurate data into different research studies on clinical care.

For example, when Mathy evaluates the patient's progress in terms of speech, saliva control and swallowing, a score of 4 in the area of speech indicates normal speech processes, while a 0 means the patient has lost all useful speech.

By comparing the scores for the most recent visit with those from the initial diagnosis, Mathy can consider whether it's time for such medical interventions as a PEG tube for nourishment or respiratory assistance.

Mathy also refers to the flow sheet to determine the person's level of knowledge of these interventions, using a similar scale.

Each patient's chart contains several flow sheets: Mathy's speech, swallowing and nutrition evaluation; the motor neuron disease evaluation form used by Sivakumar; and flow sheets to document psychosocial management, respiratory therapy, and physical and occupational therapy.

"We always have notes," Sivakumar says. "But what exactly was done from visit to visit can be difficult to put together. That's why I developed the flow sheets, which are easier to follow."

Conserving Energy

Simplifying the documentation process cuts down on the time team members spend doing paperwork. The team approach also helps patients conserve precious energy.

"I think it's great," says Carol Vincent, who received her ALS diagnosis in October 1999. "It takes a while to do everything, but it sure beats having to go from place to place — especially in the summer when it gets so hot around here."

Rita Yorke, a retired administrator for the state of Arizona, says she actually looks forward to going to the clinic, accompanied by her son, Don Pollard.

Deborah Taylor is a physical therapist.

"We know we are going to spend most of the morning here," she says. "So we usually make plans for lunch and then we go to a movie or something afterwards — make a day of it."

Yorke, who received her diagnosis in November 1999, started going to the MDA/ALS Center about a year ago when her health insurance changed.

"I've been very happy with the way everyone on the team treats me," she says.

To Yorke, the team approach is more than just a matter of convenience.

"The biggest difference is that each person who sees you is more in tune with the bigger picture of your life," she says. "You don't get that when you have to go from here to there to see different doctors and therapists."

Yorke also appreciates the work done by MDA. "They help so much, just by taking care of all the insurance stuff. All I have to do is show up, really, and they figure out where I am, what I need and how to go about getting it."

Insurance and the Team Approach

One of the key players on Sivakumar's team is office manager Sue Wilson, who has the unenviable task of trying to "sell" the logic of the team approach to a number of health insurance companies. And the center deals with almost as many different companies as there are patients.

Respiratory therapist Graham measures Yorke's respiration.

Wilson sees herself as a translator of sorts, helping to bridge the communication gap between people who speak and understand medical-ese or bureaucrat-ese, and the language of human beings who live with ALS on an everyday basis.

A key element of Wilson's strategy is to invite health care providers and insurance company representatives to see the team approach firsthand.

"I try to get blanket authorizations for the whole team, but some companies won't support that," she says. "I just think they need to be made aware of the real impact that their decisions have on families. I once had a rep from a company tell me that he couldn't come because he couldn't let himself become emotionally involved."

Probably not the smartest thing to say to a woman who's spent 35 years battling health insurance companies on behalf of doctors and their patients.

"That was one of the few times when I really lost it," she recalls. "I said, 'Oh no you don't. You are not going to just sit in an office and not be touched by what I have to show you.'"

Wilson sees the team approach as a return to the days when health care was more personal, albeit less technologically advanced.

Meanwhile Back at the Clinic

Among Sivakumar's patients, the consensus is clear: The multidisciplinary approach to ALS treatment works well.

One woman, who doesn't speak English, expressed her appreciation of Sivakumar and his team with a pack of homemade flour tortillas.

"Now I'm being paid in kind," he quips.

Clearly, one of the keys to the center's success is Sivakumar's intense desire to treat patients — not just their disease. And the director's philosophy is evident in each team member's attitude.

"Based on the disabilities caused by ALS, we tried to develop [team members] who are interested in the disease," Sivakumar explains. "We are also trying to develop a standard for care — how we would assess people, how and when to intervene — using nationally accepted standards.

"Obviously there is no cure," Sivakumar acknowledges. "But we're trying to design and implement supportive measures which will help people at least partially overcome the disabilities, while we await advances in curative therapy."

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STEM CELL THERAPY RESEARCH TAKING SEVERAL PATHS

Last year, a research group based at Johns Hopkins University in Baltimore made headlines by injecting stem cells into rodents paralyzed by an ALS-like disease — and restoring movement.

Those experiments raised hopes that stem cells could be used to replace or repair the muscle-controlling nerve cells (motor neurons) damaged by ALS. But much work needs to be done before this cell therapy can be tested in people, said Jeffrey Rothstein, lead researcher on the experiments and co-director of the MDA/ALS Center at Johns Hopkins.

"We need to know: Are stem cells safe? Which ones are the best? How do you deliver them? How do they work, and what's the expected outcome?" Rothstein said.

Recently, scientists have begun to tackle those questions, and they've come up with some encouraging answers.

Are They Safe?

The power of stem cells — their ability to divide and generate many different cell types — has many scientists worried that they could multiply uncontrollably and form tumors.

Rothstein's team, along with a group led by Ted Teng at Harvard Medical School in Boston, have begun to probe stem cell safety by shifting their experiments from rodents to animals that more closely resemble humans.

At the annual Society for Neuroscience meeting held in San Diego last month, the researchers showed they could give monkeys an ALS-like condition by injecting a plant-derived toxin called ricin into nerves in the monkeys' legs. The ricin kills motor neurons in the part of the spinal cord connected to those nerves, causing paralysis of the injected leg.

When the researchers injected stem cells into the fluid-filled space within the spinal cord, some of the cells appeared to incorporate into the spinal cord, and none appeared in other tissues far away from the site of delivery — a good sign that the cells won't disperse and form tumors.

"Six months after stem cell delivery, there's no obvious adverse effect. The cells don't do anything toxic to the spinal cord," Rothstein said.

"But what everyone really wants to know is: Did the cells do any good?" he admitted. "We do know there's some improvement in the physiological properties of the limb, but that's really not enough to hang our hat on yet."

Making Neurons

Before moving to the clinic, Rothstein and other ALS researchers are also trying to figure out which stem cells pack the most punch for repairing the damaged spinal cord.

One obvious way to use stem cells for ALS treatment would be to turn them into replacement neurons. Another option might be to save existing neurons by turning stem cells into astrocytes or blood cells.

Rothstein and Teng have tested different kinds of stem cells — from mice and humans, from different tissues and different stages of development — with various results.

At the SFN meeting, Teng reported that when human neural stem cells (those that will become nerve cells, or neurons) were transplanted into ricin-injected monkeys, the cells appeared to become neurons and make connections with other neurons in the spinal cord.

Another group, led by Alison Willing at the University of South Florida in Tampa, has been investigating human NT neurons — a laboratory-grown line of cells that aren't really stem cells, but can divide to produce neurons.

Willing's group transplanted those cells into the spinal cords of mice with the familial version of ALS, and found "striking results," she said. When treated early in the disease, the mice developed ALS one month later and lived two weeks longer than expected. When given to mice in advanced stages of ALS, the transplants didn't affect survival but slowed progression of the disease.

Human NT neurons are already FDA-approved for clinical trials in stroke patients, so they could be fast-tracked into ALS trials, Willing said.

Replacement vs. Repair

Early in the course of stem cell research, many scientists envisioned using stem cells to replace cells that were lost to disease.

But Rothstein's first experiments in mice with ALS suggested that the transplanted cells weren't filling in for missing motor neurons. Instead, they seemed to help repair or protect motor neurons that were at death's door.

Given that insight, many ALS researchers are probing stem cells for their ability to become other cell types that might stave off neuronal damage.

Robert Brown, director of the MDA/ALS Center at Massachusetts General Hospital in Boston, is investigating the use of stem cells derived from human umbilical cords. Those cells can probably become neurons, as well as a number of other cell types, including red blood cells and white blood cells (immune cells).

At the International Symposium on ALS/Motor Neuron Disease held in Oakland, Calif., in November, Brown reported that a simple intravenous injection of the "cord blood" cells prolonged survival in mice with familial ALS. The cells' mode of action isn't clear — given recent evidence linking ALS to autoimmunity (a self-directed attack of the immune system), there's speculation that they might have worked by revamping the immune system.

MDA grantee Nicholas Maragakis of Johns Hopkins is taking another approach, using cells called glial-restricted precursors. Those cells are destined to become astrocytes — cells in the brain and spinal cord that nourish and protect neurons, in part by shielding them from the potentially toxic brain chemical glutamate.

At the SFN meeting, Maragakis reported that by transplanting glial-restricted precursors into a piece of rat spinal cord, he could protect motor neurons in the cord from an overexposure to glutamate. Soon, he plans to test the cells in mice with ALS.

"It's an entirely different approach," Maragakis said. "It combines stem cells with what we know about glutamate as a toxin. We're interested in protecting neurons that are still there because we think that's easier than trying to replace neurons that are dead."

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ALS RESEARCH ROUNDUP

RATS WITH ALS

Researchers in Boston and Sendai, Japan, have created the first rats with ALS, as reported in the Dec. 1 issue of the Journal of Neuroscience. The rats, bred to have two different mutations in the SOD1 gene, both of which have been found to cause ALS in humans, will provide researchers with a significant new tool for studying the disease.

Robert Brown

Robert Brown, a neuromuscular disease specialist who directs the MDA/ALS Center at Massachusetts General Hospital in Boston, was on the study team and is enthusiastic about the rats' potential contribution to understanding ALS.

Brown noted that the rat offers several advantages over the current mouse models of the disease.

"First, it is possible in the rat to withdraw spinal fluid," he said. "This allows monitoring of spinal fluid over the course of the disease in the same animal" for biomarkers (indicators of biologic activities).

The rat's size also permits experiments that are difficult in the mouse, including infusion of drugs into the spinal fluid and injections of stem cells into the spinal cord.

NEW GENES

Researchers in Paris and Montpellier, France, Boston and Montreal have identified a small genetic region on chromosome 18 that they say harbors a gene that, when flawed, can cause ALS. When found, the precise gene is likely to provide researchers with further insight into the disease, researchers say.

MDA grantee Guy Rouleau at Montreal General Hospital Research Institute and McGill University in Montreal was among the scientists on this team, as was Robert Brown, of Massachusetts General. The study is in the January 2002 issue of the American Journal of Human Genetics and was published in the journal's Nov. 9 electronic edition.

Meanwhile, scientists in Philadelphia, Ann Arbor, Mich., and Istanbul, Turkey, have combined their talents to identify a gene that, when flawed, underlies hereditary spastic paraplegia, a disorder involving progressive paralysis and tightness of the leg muscles. The gene carries instructions for a protein dubbed atlastin.

Team member Terry Heiman-Patterson, an MDA grantee and director of the MDA/ALS Center of Hope at MCP Hahnemann in Philadelphia, believes the gene discovery may have relevance to ALS because of its importance to a disorder of the neuromuscular system.

"The identification of genes that cause motor neuron [muscle-controlling nerve cell] dysfunction gives us insight into pathways that are important to the motor system and that therefore contain targets for manipulation," Heiman-Patterson said.

The atlastin gene study appears in the Nov. 1 issue of the journal Nature Genetics.

SYNTHETIC GENE

A laboratory-engineered gene made from pieces of two existing genes has been found to protect mice against a type of nerve injury known as Wallerian degeneration, which is normally seen after injury in animals and people. Wallerian degeneration is thought to be very similar to some of the degeneration seen in ALS, according to biochemist Michael Coleman, who was on the study team.

"We are still working out the protective mechanism," said Coleman, a biochemist at the Institute for Genetics in Cologne, Germany. He was part of a team that published its findings in the December issue of Nature Neuroscience.

The scientists began developing the synthetic gene after they discovered that certain mice known as Wld(S) — for "slow Wallerian degeneration" — enjoyed a natural protection against nerve-cell injury. These mice naturally possessed a gene formed by the fusion of two genes and also retained their copies of the original genes, Coleman said.

The new gene appeared to lead to production of a neuroprotective protein. So, the scientists recreated the new, fused gene in the laboratory and bred mice with it. These mice showed unexpected protection from nerve injury.

"It is quite possible that different genetic changes to either of the two normal genes could cause a similar type of protection," Coleman said. He suggested that it "may be possible to design drugs that alter the activity of the two normal genes or their proteins and thus prevent or delay neurodegeneration."

IMMUNE SYSTEM CHEMICAL

MDA-supported experiments at McGill University in Montreal, Quebec, Canada, have suggested that an immune system chemical known as TNF-alpha may play a role in the destruction of nerve cells in ALS. TNF-alpha is a key player in inflammation, a biochemical process involving tissue destruction by the immune system (see "Simply Stated," Quest, vol. 8, no. 3).

Blocking TNF-alpha and TNF-beta has shown some success in the treatment of rheumatoid arthritis, an inflammatory disease in which immune system activity is abnormal.

Janice Robertson, neuroscientist at McGill and an investigator on this study, said the drug minocycline (Minocin), which is already being studied in ALS, could help defeat the inflammatory response that she believes plays a role in ALS. MDA grantee Heather Durham at McGill's Montreal Neurological Institute was on the study team, which published its findings in the Oct. 15 issue of the Journal of Cell Biology.

SPROUTING NEURONS

Researchers have found that mice carrying a mutation in the SOD1 gene (known to cause ALS in humans) showed a possible benefit from treatment with a neurophilin ligand. These compounds are small molecules that increase sprouting of neurites, the fingerlike projections through which nerve cells send and receive signals.

The research team, funded by Vertex Pharmaceuticals of Cambridge, Mass., found that the compounds known as V-13,670 increased the number of neurites projecting from motor neurons toward muscles to a greater degree than was seen in the untreated mice. (Even untreated animals generally show an increase in such neurites, probably as a compensation for death of nearby nerve cells.)

"One might anticipate that a treatment that enhances the capacity of the ALS motor neuron to sprout might slow the overall process of motor neuron degeneration and death," the authors write in the Nov. 27 issue of Neurology. "On the other hand, one could also speculate that forced sprouting of the dying motor neuron might have an overall adverse effect on [the] rate of death of the cell."

The study team included Robert Brown and Merit Cudkowicz of the MDA/ALS Center at Massachusetts General, and Jeremy Shefner, director of the MDA/ALS Center at SUNY Upstate Medical University in Syracuse, N.Y.

GENE THERAPY

GDNF (glial-derived neurotrophic factor), a natural nervous system chemical that has neuroprotective effects, can be delivered to mouse muscles via gene therapy and may offer some benefit to nerve cells, says MDA grantee Gyula Acsadi of the Department of Pediatrics at Wayne State University in Detroit.

Using two different viruses — adenovirus and adeno-associated virus — as gene delivery vehicles, researchers found that GDNF could end up in nerve cells in the spinal cords of mice with ALS after being delivered to muscle cells. Preliminary analysis suggests some slowing of functional deterioration and some improvement in survival time.

These early results were presented at the World Federation of Neurology and 12th International Symposium on ALS/MND in Oakland, Calif., in November.

PREDISPOSING FACTORS

A large study of genetic and environmental risk factors in ALS is still in need of participants, says clinical nurse specialist Nailah Siddique at Northwestern University in Chicago.

Participation in the study requires blood samples from the person with ALS and from affected or unaffected siblings or parents, and filling out a questionnaire that may reveal environmental factors related to ALS.

Travel isn't necessary, as the researchers can send a blood-drawing kit to the patient's own physician.

For more information, see "Researchers Need Your Help to Solve Riddle of ALS," The ALS Newsletter, vol. 4, no. 6.

To inquire about participation, contact Siddique at (312) 503-2712 or nsiddique@northwestern.edu; or Lisa Dellefave at (312) 503-0154 or 1-dellefave@northwestern.edu.

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GLUTAMATE TRANSPORTER COULD BE KEY TO BETTER DRUGS

MDA-funded scientists say that finding better drugs to clean up toxic levels of glutamate could be the key to treating ALS.

In a study on mice, the scientists showed that a genetic boost of "glutamate transporter" protein offered more protection against ALS than any drug treatment that's been tested so far. In fact, it worked several times better than the anti-glutamate drug riluzole, the only FDA-approved drug for ALS.

MDA grantees Jeffrey Rothstein of Johns Hopkins University in Baltimore and Margaret Sutherland of George Washington University in Washington presented the study at the Society for Neuroscience meeting in San Diego last month.

How Astrocytes Use EAAT2 to Protect Neurons Neurons release glutamate to communicate with other neurons, but too much glutamate can be harmful. The glutamate transporter EAAT2, found on the surface of astrocytes, protects neurons by vacuuming up excess glutamate.

Glutamate normally acts as a chemical messenger between neurons, but at high levels, it can be toxic. Cells called astrocytes use the glutamate transporter — known as EAAT2 — to vacuum up excess glutamate and protect neurons. But for reasons that aren't clear, many people with ALS have reduced levels of the EAAT2 protein, and the resulting accumulation of glutamate appears to damage motor neurons.

Riluzole (Rilutek) works by blocking glutamate release. But it extends life by just a few months in people with the disease and by two weeks in mice with the disease.

Rothstein and Sutherland hope to come up with more potent drugs that work by activating EAAT2. As a first test of that strategy, they introduced extra copies of the EAAT2 gene into SOD1 mice (which normally develop ALS).

"With the glutamate transporter, we can increase mouse survival not by two weeks [as with Rilutek], but by a minimum of two months and a maximum of one and a half years," Rothstein reported.

Rothstein and Sutherland also used a fluorescent tag to visualize the EAAT2 protein, and found that astrocytes change their EAAT2 production in response to cues from motor neurons. That setup should allow the team to quickly screen for drugs that increase EAAT2 production, Sutherland said.

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Bill Ross and the Art of Living With ALS

It's been said that every cloud has a silver lining — even though it might be difficult to find any brightness in a cloud as dark as ALS.

William Ross

William M. Ross — writer, artist and teacher — of Bronxville, N.Y., has managed to find more than one silver lining in his ALS "cloud."

For example, he reconnected with a friend he hadn't seen in more than 40 years.

"Eddie Lopez is one of the miracle friends who's come into my life," Ross says. "He heard of my illness through the grapevine and called me up out of nowhere. Since then, we've resumed our 'best of friends' friendship and he comes over every week and helps me."

Ross credits Lopez with enabling him to pursue his greatest passion: painting.

"Eddie built my easel," Ross says. "It goes forward, back, up, down — it does everything but cook."

Ross, 64, recently had two watercolor paintings accepted by the MDA Art Collection.

"Twilight in Paradise" depicts a lone cowboy riding in a hilly range, watching wild horses frolic in the distance. "Heaven on a Summer Night" captures a minor-league baseball game.

And if you look closely, you'll see a tip of Ross' cap to Lopez.

Lopez's father was a taxi driver who played minor-league baseball in Puerto Rico and was known as "Montano," Ross explains. "So in order to show my love for my friend — because he so admires his father, who was an admirable human being — I put that 'Montano Taxi' sign on the right field fence" in the upper-left section of the painting."

Publisher and Playwright

William Ross demonstrates his mouth-painting technique at his Bronxville, N.Y., home.

To the best of his knowledge, Ross has never produced music videos for MTV — but that's possibly the only creative thing he hasn't done.

Ross, who holds a doctorate in English and worked primarily as a high school English teacher, has written articles for Writer's Digest and contributed to several textbooks published by Prentice-Hall. Perhaps his greatest writing success has come as a playwright, with two of his plays ("Smart-Rage" and "Three Names for Murder") having been produced by New York's Royal Court Repertory.

But the work that gives Ross the most satisfaction is his children's novel, "The Ticket to Harmony," which he published in 1994 through his own company, Trolley Car Books. He sold 2,000 copies through schools and writing seminars.

"I used to visit schools and talk to the kids about writing," he said. "They would read the book, and I'd talk to them afterwards. They'd ask me all sorts of questions and I'd show them some of the artwork that I did on the cover.

"I designed that whole book, by the way. There's nothing in there that I didn't do except print it."

A Premonition

Like most people, Ross began to experience the symptoms of ALS before he received the actual diagnosis, in January 1999.

But unlike most people, Ross wasn't exactly taken by surprise.

"The funny thing is, I'd always had a premonition about ALS, long before I got it," he relates. "I knew what it was and I kind of had a dread. I mean, like anyone else I dreaded all diseases, but ALS was the one that particularly kept buzzing in my mind."

Ross attributes his fear of ALS to his lifelong claustrophobia.

"I've always been afraid of ALS because it's a claustrophobic kind of a disease. In other words, it precisely locks you up inside your body," he explains.

In a twist of irony worthy of one of his plays, Ross finds that the reality of ALS doesn't quite match the monster he'd always feared.

"ALS hasn't made me spastic. I'm not stiff as a board, which was what I'd thought," he says. "I still can move — it's just that other people have to move me. But it isn't like I'm just stuck here forever."

Getting services at the Eleanor and Lou Gehrig MDA/ALS Center, located at the Columbia Presbyterian Medical Center in New York — on the ninth floor — has helped him conquer claustrophobia.

"That sure helped me get over my fear of elevators," he laughs ruefully.

'I Have a Life to Live'

Ross says that Hiroshi Mitsumoto, director of the Gehrig center, has told him his ALS is atypical, manifesting itself primarily in his lower motor neurons. So while his only mobility is a little movement in his hands, he's still pleased that he's shown no signs of upper motor neuron impairment, which would involve some spasticity.

"That would really be catastrophic, because then I couldn't paint," he explains. "And I'm not just a Sunday painter to keep myself busy. I regard myself as a serious painter."

So serious and so busy that he has neither the time, nor the inclination, to feel sorry for himself.

"Look at it this way," he begins. "I have ALS. I'm sitting in a chair here, and I can't move. On the other hand, look at what I have. I've got a wife [Marie] of 38 years who loves me, and whom I love dearly, who's just wonderful. I've got four wonderful kids — all of them honorable, wonderful people. I've got four grandchildren.

"I have a wonderful aide, and wonderful friends to beat the band. I've got a talent that keeps me busy all day that I enjoy.

"I've had a very, very full life," he continues. "I've had plays in these little theaters down in Manhattan and I've written a book. Any one of those, most people in the world would give their eyeteeth for. What else do I want? Where's my complaint?"

Heaven on a Summer Night, William Ross

A deeply spiritual man, Ross considers himself far too busy counting the blessings he has to worry about what — if anything — he's lost.

"I'm not in denial," he asserts. "I know very well what ALS is and what it's going to do and all that. But I'm so surrounded with love, there's nothing that I did when I was well that I don't do now. I just have to find different ways of doing things."

He also counts MDA among his blessings.

"They tell me, 'Bill, when this muscle zigs, we're going to show you how to zag.' Their attitude is that, even though you have ALS, you can lead a very full life," he says of the MDA staff and experts he's encountered.

Today, Ross is working on a new painting — one that will reflect his newly acquired ability to paint with the brush held in his mouth.

"I chuckle when I imagine an art critic who doesn't know I have ALS writing, 'Bill Ross' early works were tight and controlled, but his later works show a remarkable fluidity, indicating that Ross has finally found his soul.'"

And the subject of his upcoming work will be none other than Lou Gehrig himself.

"He's an omnipresent person in my life, especially now that I've got the illness," Ross says. "He was a nice fellow, too. A very interesting guy, and a very good-looking man, too."

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A FRIEND AT THE TOP

Bill and Mary Sweeney of Willis, Texas, knew they were taking a special trip when they traveled to the East Coast for a family reunion this summer. But the trip became positively unforgettable when a family friend was able to arrange a visit to the White House and a meeting with President Bush.

The Sweeneys (Bill, Mary and daughters Lauren, 12, and Leah, 9) were treated to a 20-minute meeting with the president that included time for photos and autographs, and a detailed tour of the Oval Office and the White House Rose Garden.

Bill Sweeney, who learned he had ALS in 1997, said he was most impressed with how much Bush knew about ALS and his computer equipment and head mouse.

"I found him to be very humble and down to earth," he said of the president. "He said that he was pleased that Medicare was going to assist people in my situation by helping pay for this expensive equipment."

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Give It A Rest

Tips for Sleep-Deprived Caregivers

The National Sleep Foundation recently confirmed what Mom probably told you a long time ago: The average adult requires at least eight hours of sound sleep a night.

But to caregivers who are up and down all night helping their loved ones with serious conditions like ALS, that may sound like a laughable ideal.

Unfortunately, chronically sleep-deprived people don't laugh all that much. A recent University of Texas study of 51 caregivers of terminally ill family members found a clear correlation between lack of sleep and severe depression.

"A caregiver's sleep levels were the best predictor of caregiver depression levels," says the study's lead author, Patricia Carter of the UT School of Nursing in Austin.

Besides depression, sleep-deficit symptoms can range from misplacing the car keys to crashing the car. Researchers say an ongoing lack of sleep can cause: forgetfulness, lowered alertness, reduced creativity, inability to speak and write clearly, lowered resistance to disease, unwanted weight gain, and increased risk of stroke, heart attack and adult-onset diabetes. Sleep-deprived people also are more likely to verbally and physically abuse their children, and are more prone to falling asleep at the wheel.

Great — something else to worry about while staring at the ceiling at 3 a.m., right? Wrong. It's possible to get more rest while still getting up to care for your loved one with ALS.

Actually, getting up several times a night isn't as big a problem as not being able to fall back to sleep quickly afterwards, says James Maas, a Cornell University (Ithaca, N.Y.) sleep expert and author of Power Sleep: The Revolutionary Program That Prepares Your Mind for Peak Performance, published by Harper-Collins.

Maas and other sleep experts offer these suggestions for improving the quality and quantity of sleep:

Check out your sleep space. Is your bedroom actually a restful place? An uncomfortable mattress, snoring spouse, too much light, being too hot or too cold, pets who jump on and off the bed, and outside noises all are subtle distractions that make it hard to settle back down.

Don't live with it — take steps to change it! A fan that creates white noise, eyeshades, putting the pets elsewhere or investing in a great mattress all can improve your sleep — and by extension, your life.

Three on, three off. If it's possible, share the nighttime caregiving duties. For optimum sleep benefits, Maas recommends a three-nights-on, three-nights-off schedule, rather than switching with someone every other night.

If you've tried all of the above — and then some — and still can't get enough rest, talk to your doctor. Not all caregiver sleep problems are caused by stress or getting up in the night. There may be an underlying physical problem that can be treated so you can get the zzzzz's you need.

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CAREGIVERS SPOTLIGHTED IN TWO NEW BOOKS

The Fearless Caregiver: How to Get the Best Care for Your Loved One and Still Have a Life of Your Own, by Gary Barg, Editor-in-Chief, Today's Caregiver magazine. 264 pages, 2001, $21.95. Capital Books, www.capital-books.com, (800) 758-3756.

Gary Barg was a successful video producer in Atlanta when he was abruptly thrust into the world of caregiving through the illnesses of his father and grandparents. As he helped his mother sort through the tangle of information about services, treatments and legal necessities, he found himself wishing for a central resource for caregivers. Since none existed, he decided to create it.

In 1995, Barg founded Today's Caregiver magazine, with an accompanying online site, www.caregiver.com, that offers information and gives caregivers a chance to connect.

The Fearless Caregiver is one more brick in Barg's efforts to build a solid support structure for caregivers.

The book is really a collection of articles by Barg and more than 30 other experts: doctors, nurses, psychologists, physical therapists, counselors, clinical social workers, lawyers, financial planners, spiritual leaders and — last but certainly not least — experienced caregivers.

Supportive and often laced with humor, the articles guide the reader through such practical matters as talking to doctors, dealing with contractors, coping with depression and fear (yours and your loved one's), and getting through the holidays.

Barg's book is heavily slanted toward caregivers of people with Alzheimer's disease, and there are no references to ALS. However, its encouraging tone, humor, practical advice and unblinking approach to the realities of caregiving make up for this deficit. It's sort of like a support group in a book, and as such is a valuable addition to a caregiver's toolbox.

Caregivers and Personal Assistants: How to Find, Hire and Manage the People Who Help You (Or Your Loved One!), by Alfred H. DeGraff, revised third edition, 505 pages, 2002, $24.95. Saratoga Access Publications, www.saratoga-publications.com, (970) 484-5531.

Alfred DeGraff's revised book — to be released in March — covers in thorough detail every imaginable aspect of working with caregivers and personal assistants.

DeGraff, who uses a motorized wheelchair because of a spinal cord injury, draws extensive information from his own experiences and from talking with countless others.

He advises readers to approach hiring and keeping personal assistants the way they'd approach running a small business — in this case a lifelong business in which failure isn't an option. He provides advice for operating the "business" in the most cost-effective and efficient fashion possible.

The book's sections examine such topics as the different kinds of assistance options available and management strategies. It also offers extras such as how to write a catchy classified ad to attract a quality personal assistant, and tips on how to assert yourself.

The impressive amount of information in this book might seem overwhelming to some, but it's carefully organized and indexed to be of help in almost every situation.

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Little Rock Olympic Torch Bearer Also Has ALS

The Olympic torch will arrive at the 2002 Winter Olympic Games on Feb. 8, having been relayed person-to-person over a 13,500-mile meandering route across the United States. For one-quarter of one of those miles, the torch was under the care of Paul Dunn of Little Rock, Ark.

Dunn, 30, a former life insurance salesman and avid athlete, received a diagnosis of ALS in May 2000. Despite his weakened condition, he was the first person a friend thought about when Coca-Cola announced it was seeking "inspiring people" to carry the torch.

The friend put out the word on the Internet and more than 150 people sent in letters nominating Dunn for the honor. He was one of 11,500 torch bearers chosen from among 210,000 nominees.

On Dec. 13, the torch was attached to Dunn's power wheelchair and he carefully bore it just a little closer to its final destination in Salt Lake City.

"I'm very honored and humbled that I was nominated to do this," he said.

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