NEW GDNF TRIAL TO PUT DRUG IN BRAIN

A new clinical trial of glial-derived neurotrophic factor (GDNF) will test the drug using a direct brain delivery route, according to Jeanne Flynn, senior manager of professional services at Amgen Pharmaceuticals in Thousand Oaks, Calif.

GDNF will be delivered into the brain's ventricles via an access port implanted under the scalp.

The technique is called "intracerebroventricular" (ICV) administration and has been used in a clinical trial for Parkinson's disease. The drug will be injected into an access port [under the scalp] and will enter the fluid in the brain's ventricles -- open spaces in the brain. The fluid bathes the surrounding brain tissue and is connected to the spinal fluid.

The investigators say they expect more of the drug to enter the central nervous system (brain and spinal cord) than with subcutaneous (under the skin) administration.

Six sites have been chosen for the trial. They are the University of Miami Center; the Emory Clinic in Atlanta; the University of Rochester (N.Y.) Medical Center; the Cleveland Clinic Foundation; the University of Wisconsin Medical Center in Madison; and the University of Alberta Medical Center in Canada. The Miami, Atlanta, and Rochester centers are MDA clinics. The Madison site is an MDA/ALS center.

Flynn said the GDNF trial is technically still open, although they have enough patients for the first stage. As each dosage level of GDNF proves safe, she said, new patients will be accepted at higher dosage levels.

To register for the trial or for more information, call (800) 77-AMGEN. You can visit Amgen's web site at http://www.amgen.com for further developments.

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NEW DRUG APPLICATION FILED FOR MYOTROPHIN

On Feb. 11 [1997], the drug companies Cephalon (West Chester, Pa.) and Chiron (Emeryville, Calif.) submitted a New Drug Application to the Food and Drug Administration (FDA) for their ALS drug Myotrophin.

Approval of the New Drug Application is needed before Myotrophin can be marketed for the treatment of ALS. Since last June, the companies have had FDA approval for an expanded access program, a limited go-ahead that has allowed them to give away Myotrophin to randomly selected ALS patients. The drug is not yet on the market.

"We've been told the application will be given a priority review, which usually means six months," said Kori Beer, manager of corporate communications at Cephalon. Beer said the expanded access program is continuing, with new patient slots opening monthly as patients leave the program.

Myotrophin (insulin-like growth factor 1) is a neurotrophic factor that acts somewhat like insulin. It has to be injected under the skin twice a day, an hour after meals. Cephalon has made patient education a priority, Beer said, and has videos and print material on how to inject Myotrophin. Patients on Myotrophin are also entitled to free visits from a home health nurse to learn injection technique.

To register for the expanded access program or get information about Myotrophin, call (800) 896-5855.

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BDNF FAILS ONE TEST, ANOTHER IN THE WORKS

Brain-derived neurotrophic factor (BDNF) didn't show a benefit in ALS when compared with a placebo (inert substance) in a phase 3 trial that included 1,135 people, the drug companies Amgen (Thousand Oaks, Calif.) and Regeneron (Tarrytown, N.Y.) announced recently. BDNF and the placebo were injected subcutaneously (under the skin) in this trial.

At the end of six months, there were no significant differences in respiratory function between the treated group and the placebo group. At nine months, there were no differences in survival between the groups. These were the primary measures evaluated.

BDNF will be injected into spinal fluid in a pilot study in Chicago. The drug will enter the fluid via an access port implanted under the skin in the abdomen. The system is manufactured by Medtronic of Minneapolis.

The drug was safe and well tolerated, with injection site reactions and bowel urgency or diarrhea the most frequently reported side effects.

Amgen and Regeneron will pursue the study of BDNF in ALS, but doctors will inject the substance into the fluid surrounding the spinal cord (cerebrospinal fluid, or CSF). This form of drug delivery is called "intrathecal," or IT. The drug will enter the fluid via an access port implanted under the skin in the abdomen. The system is manufactured by Medtronic of Minneapolis.

Several experts have suggested that neurotrophic factors will have to be injected near the brain or spinal cord to be effective, because little of these substances can reach the central nervous system (brain and spinal cord) when they are injected under the skin at the periphery of the body.

So far, only one site, the MDA clinic at Rush-Presbyterian-St. Luke's Medical Center in Chicago, has been chosen for the IT BDNF trial. Jeanne Flynn, Amgen's senior manager of professional services, said no further recruiting for this pilot trial will be done at this time.

Patients who have been in the sub-cu trial of BDNF are urged to contact the investigators at their trial site with questions about continuing subcutaneous BDNF or any other questions related to BDNF. Anyone can call Amgen's information line at (800) 77-AMGEN or visit Amgen's web site at http://www.amgen.com for further developments.

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MDA ADDS NEW ALS CENTERS IN BALTIMORE, DALLAS, DENVER

MDA has designated three new MDA/ALS research and clinical centers at leading universities in Baltimore, Dallas and Denver. The appointments, made in February, bring to 14 the total roster of MDA-funded centers dedicated to ALS research and medical care.

The MDA/ALS Center at Johns Hopkins University School of Medicine in Baltimore is one of the newly designated facilities. Dr. Daniel B. Drachman, professor of neurology and neurosciences and director of the neuromuscular unit at Johns Hopkins, and Dr. Jeffrey D. Rothstein, professor of neurology, will be co-directors.

Drachman is a member of MDA's Medical Advisory Committee and co-director of MDA's clinic at Johns Hopkins Hospital, which offers medical services to anyone affected by any of the 40 neuromuscular diseases in MDA's program.

Rothstein is an MDA-funded researcher whose studies revealed the role of excess glutamate in ALS. The finding led to the development of riluzole, the first FDA-approved drug used in treatment of the disease.

Over some 30 years of studying ALS, scientists at Johns Hopkins have conducted clinical trials of many potential treatments and plan several new trials. Other areas of ALS study at Johns Hopkins include free radical involvement, glutamate transporters and gene therapy to correct the SOD1 genetic mutation known to cause a form of ALS. The MDA/ALS Center can be reached at (410) 955-6435.

Dr. Steven P. Ringel was named director of the new MDA/ALS Center at the University of Colorado Health Sciences Center in Denver. He is also co-director of MDA's clinic at the university and author of "Neuromuscular Disorders: A Guide for Patient and Family."

At the university, Ringel is professor of neurology, director of clinical practice and director of the neuromuscular clinic. Under an MDA grant, the university is currently studying a second gene that, when defective, is linked to ALS.

Some 175 ALS patients are seen at the Denver clinic, with some participating in clinical trials. The new MDA/ALS Center can be reached at (303) 315-7221. For more information about clinical trial participation, call (303) 315-7046.

The new MDA/ALS Center at the University of Texas Southwestern Medical School in Dallas will be directed by Drs. Wilson W. Bryan and Richard J. Barohn. Barohn is associate professor of neurology at U.T. Southwestern and Bryan is an assistant professor of neurology. The two are co-directors of the MDA clinic at U.T. Southwestern.

The Dallas center serves about 150 people with ALS. U.T. Southwestern was one of five original centers in the Western ALS Study Group, a consortium of ALS clinical trial centers initiated by MDA in 1988. U.T. Southwestern is now conducting clinical trials of BDNF and gabapentin.

The new center can be reached at (214) 648-6419, or by calling the MDA Dallas office at (972) 480-0011.

MDA's other designated ALS Centers are:

• The Jerry Lewis MDA/ALS Clinical and Research Center at the University of Southern California School of Medicine in Los Angeles; Dr. W. King Engel, director
• The MDA/ALS Center at the University of California at Los Angeles; Dr. Michael C. Graves, director
• The Forbes Norris MDA/ALS Research Center at California Pacific Medical Center in San Francisco; Dr. Robert G. Miller, director
• The MDA/ALS Center at Yale University in New Haven, Conn.; Dr. Jonathan M. Goldstein, director
• The MDA/ALS Center at the University of Chicago; Dr. Raymond Roos, director
• The MDA/ALS Center at Massachusetts General Hospital in Boston; Dr. Robert H. Brown, director
• The MDA/ALS Center at Washington University School of Medicine in St. Louis, Mo.; Dr. Alan Pestronk, director
• The Eleanor and Lou Gehrig MDA/ALS Center at Columbia University in New York; Dr. Lewis P. Rowland, director
• The MDA/ALS Center at Duke University Medical Center in Durham, N.C.; Dr. Janice Massey, director
• The MDA/ALS Research and Clinical Center at Baylor College of Medicine in Houston; Dr. Stanley H. Appel, director
• The MDA/ALS Midwest Regional Research Program at the University of Wisconsin in Madison; Dr. Benjamin R. Brooks, director

While MDA/ALS centers offer highly focused programs of research and medical management directed at combating ALS, the Association also offers a full program of clinical services for ALS patients at all of its 230 hospital-affiliated clinics across the country, including participation in clinical trials of experimental treatments. The Association also sponsors dozens of research projects on ALS in the United States and abroad.

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SPINAL FLUID DELIVERY OF CNTF GETS MIXED RESULTS

Four people with ALS had ciliary neurotrophic factor (CNTF) injected into the fluid surrounding the spinal cord (intrathecal delivery) at MDA's clinic at Rush-Presbyterian-St. Luke's Medical Center in Chicago.

A previous trial of CNTF given subcutaneously (under the skin) didn't show any benefit, and patients had significant side effects.

In this phase 1 trial (for safety only), the drug was well tolerated in two patients, while the other two had head or leg pain. No patient improved, and the disease course was not slowed by the drug.

When the investigators tested levels of CNTF in the spinal fluid, they found they were much higher than those that preserved motor neurons in culture dishes. However, they don't know how much CNTF actually entered nerve cells.

Doctors commenting on the study noted that the high levels of the drug found in the spinal fluid were encouraging for this mode of drug delivery, but some also voiced caution about the drawbacks of CNTF. One doctor noted that the drug seems to cause an inflammatory reaction in the central nervous system.

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SOD1 MUTATIONS LINKED TO DISEASE DURATION

A study in the January issue of Neurology reports that particular SOD1 mutations can be correlated with duration of disease, but not age of onset, for those ALS patients with SOD1 mutations.

SOD1 is the protein which, when defective, accounts for about 15 percent of cases of familial ALS. Mutations from 158 patients from 27 families were studied. Approximately half the patients had one particular mutation, in the fourth amino acid of the SOD1 protein. These patients had the most rapid progression, living approximately one year after diagnosis. The next most common mutation was associated with survival of about five years.

None of the differences among the mutations studied could be correlated with differences in age of onset of the disease, suggesting that other, nongenetic factors may account for these differences.

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MDA GRANTEE URGES CAUTION ON ALS "TREATMENTS" IN NEWS REPORTS

Can aspirin protect neurons from damage? Can immunosuppressive drugs? Marijuana-like drugs? And what about testicular cell implants? All these have been in the news lately as "neuroprotective agents."

Dr. Jeffrey Rothstein, an MDA grantee who specializes in neuronal damage and neuronal protective strategies at Johns Hopkins University in Baltimore, urges the ALS community to interpret these studies cautiously.

"I don't want to sound negative," Rothstein said. "These studies are intriguing and worth following. However, none of them, to my knowledge, were done using an ALS model."

Rothstein said the aspirin study used cells from the cerebellum and that these aren't the cells affected in ALS. Damage to cerebellar cells follows a different pathway than the damage to motor neurons that occurs in ALS.

Many of the studies were done in animal or test-tube models of strokes, brain injury or Parkinson's disease, Rothstein said, and the cell types or mechanisms of cell damage in these conditions could differ from those found in ALS.

"A lot of these drugs are anti-inflammatory in their action," he said, "and although there is some inflammation in ALS, it probably doesn't play a major role in causing or fueling the disease."

Rothstein doesn't recommend high-dose aspirin for his patients.

"Right now, for ALS, the anti-glutamate agents, antioxidants and neurotrophic factors look more promising than anti-inflammatories, and these are getting our attention," he said.

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DR. APPEL TO GO ONLINE FOR ALS CONFERENCE

MDA-funded researcher and clinician Dr. Stanley H. Appel goes online from 11 a.m. to noon EDT on April 19 [1997] to answer questions about ALS during a live conference on the MDA Forum on CompuServe. The subject of the conference will be the current state of ALS research and treatments.

Information about ALS is available year-round on the MDA/ALS Clinic World Wide Web Site at http://www.bcm.tmc.edu/neurol/struct/als/als1.html. The site is maintained by Appel's team of health professionals at the MDA/ALS Research and Clinical Center at Baylor College of Medicine in Houston.

MDA's own official World Wide Web address is http://www.mda.org.

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BROWN SPEAKS AT DEDICATION OF NEW ALS CENTER

Dr. Robert H. Brown Jr., professor of neurology at Harvard Medical School, was the keynote speaker at the Feb. 13 [1997] ceremony dedicating the new MDA/ALS Research and Clinical Center at the University of Texas Southwestern Medical School in Dallas. Brown is a member of MDA's Medical Advisory Committee and director of MDA's ALS Center at Massachusetts General Hospital in Boston. He was one of the MDA-funded scientists who discovered in 1993 the gene flaw that is responsible for some cases of the familial form of ALS, which affects about 10 percent of those with the disease. In his remarks, he described the work leading to the discovery, and new areas of ALS research that have stemmed from it.

Here is an excerpt from his presentation:

* * * * *

It is breathtaking when one stands back and looks at what's been accomplished over the last 10 years in neuromuscular diseases. There are some 40-odd diseases that are embraced by the Muscular Dystrophy Association and of those now almost 50 percent have had their causes defined through MDA-sponsored research. That is an enormous accomplishment. That, by the way, is at a time when very often the federal government has not had the wherewithal to support the research. So, one can only enthusiastically endorse the MDA and thank it for all that it does.

About 10 years ago, working with Dr. Teepu Siddique at Northwestern University (co-director of the MDA clinic in Chicago) in an enormous team effort, we were able to encounter some 300 or 400 families in which ALS runs as a disease across many generations. This is clearly a devastating family picture.

Of course, the silver lining is that we can use molecular biology to try and track down the cause of the problem. To make a very long story short, that was what was undertaken by this collaborative team. And in 1991, an address for a gene defect was found on chromosome 21. And in 1993, to the astonishment of everyone on the team, it was found that mutations in this gene making this particular protein (superoxide dismutase 1 or SOD1) were present in many individuals who had familial ALS. So that leads one then to say: What is this protein and how can changes in it cause Lou Gehrig's disease?

It's a very modest protein. It is about 150 amino acids, which is small as proteins go, but despite the small size, it is biologically terrifically important, because this protein is made in every cell in your body. It's made in every cell in every form above the bacterium, so nature has seen fit to conserve it. And if that isn't good enough, nature has two or three other genes that make the same kind of protein.

So something about this protein is very important for normal life. There's a copper molecule which is the working ingredient of this particular molecule (SOD1). The copper interacts with a form of oxygen called superoxide anion. This is a molecule that has an extra free electron and as such it is a "free radical" and a very potentially toxic molecule, because it can interact with anything in the cell and do damage.

This substance, superoxide anion, is the price that all of us pay for breathing air to make energy. Because as we breathe air and make energy, this is a spin-off byproduct. So literally our cells are bathed in a firestorm of these free radical substances which would truly burn us up if we didn't have a lot of the molecules that defend against these potential poisonous free radicals. And that is what SOD1 does. It takes that molecule (superoxide anion) and turns it into a series of other molecules and detoxifies it.

50 + MUTATIONS

So obviously what this led us to was the idea that perhaps some abnormality in how free radicals are processed is critical in triggering motor neuron death in Lou Gehrig's disease, and that's really the first chapter in the story.

There are 54 different mutations in the (SOD1) gene which are responsible for causing only one disease and that's familial ALS. It also turns out that the way the disease behaves depends a lot on which particular part of the protein is abnormal. If you have one abnormality, sadly enough the overall survival is one year, no more. If you have another abnormality in the same protein, the survival is 20 years. So this is an important lesson for us to learn about how this disease acts, if we can understand what those two different kinds of changes in the molecule do.

It turns out that the molecule mutations are scattered all throughout SOD1. But there is one part which has never changed in the disease. So one of the biochemical assignments is this: Can we now figure out what it is about this part of the molecule that triggers the disease? That's one of the many things that we're going to use the MDA dollars to help research.

TOXICITY TRIGGERED

Let me ask this question. If there are more than 50 changes in the molecule that cause the same disease, how do they cause the disease? We don't know the answer but we think it's probably the case that what all of the different changes do is turn that protein into a poison. One way or another they make it toxic. One of the reasons we know that is because if you take the gene for the abnormal molecule and you put it in a mouse and express the abnormal molecule at very high levels, incredibly enough, the mice develop ALS. And they develop it as an adult-onset disease.

It starts in one limb and it spreads and moves up the spinal cord just the way it does in patients. So, that at least gives one some insight as to how the molecule works.

One of the issues that we are struggling with is this question: Why are motor neurons selectively targeted by these mutations (in SOD1)? We've already made the argument that this protein is expressed in every cell in the body, yet Lou Gehrig's disease has an exquisite specificity for attacking only one type of neuron, less than 1 percent of all the neurons in the brain, the motor neurons. How can that be? We think part of the answer is located in the complex anatomy of the motor neuron, which is an enormous cell with an enormous process which is bombarded all the time with excitatory synaptic stimuli from compounds like glutamate.

One of the first published studies, by Dr. Mark Gurney (MDA-funded researcher at Northwestern University in Chicago), found that when he gives Vitamin E to the mice, and this is a strong free-radical sponge, the mice show a delay in the onset of their illness. So a free-radical sponge slows the way the disease starts. But once it starts, it goes just as fast. On the other hand, when he gives a drug which we all know, riluzole, which prevents glutamate excitotoxicity, the mice got sick at just the same time but once they got sick, the disease course was slower.

DIFFERENT SOLUTIONS

So what this shows you is, first of all, there are two drugs that we ought to think about in this disease and, secondly, that with drugs you can begin to tease out different parts of the illness. It is beginning to look like we may want to distinguish between factors that cause or initiate the disease, and then a different set of factors that keep it going once it starts.

There may be yet another set of factors That's important in letting the disease spread. We could call these dissemination factors. The disease tends to start in one spot or part of the body and then move up or across. The reason that we care about this is it has direct bearing on treatment. If we can distinguish the chemistry that causes the disease at the start from that which sustains, from that which makes it spread, then we may be able to come up with new ideas about how to treat each phase of the illness.

What I am saying is, there may not be one treatment for ALS, as has been found to be the case in cancer. It may take many treatments treating different aspects of the disease. And what I think is evolving here is a way in which we can think about different aspects of this disease. The final cause of why motor neurons die, once these things are started, is not known, but there is an exciting new set of ideas being investigated in that realm as well. So I am actually quite upbeat in terms of at least what is coming into the pipeline as new drugs to think about treating different parts of this illness.

MORE GENETIC FINDINGS

There has also continued to be real progress in understanding other possible causes of genetic forms of motor neuron disease. In ALS, for example, it is now appreciated that mutations in another gene which makes the cyto-skeletal proteins called neurofilaments can be associated with the illness in some people, and these mutations are just about as common as the SOD1 mutations.

As recently as this November, Dr. Phillip Chance (MDA grantee at Children's Hospital of Philadelphia) reported that in a juvenile-onset type of ALS, he found an address for a gene on chromosome 9. We don't know what the gene is, but that is now looming large in the landscape, and it is another mandate for us all, to find the resources to identify that.

I will just share with you part of my own clinical story. We have had the honor of collaborating with very sharp neurologists in Tunis (in North Africa) who have helped us find another chromosomal address for ALS. There is a juvenile-onset form of Lou Gehrig's disease in Tunis, that starts about the age of 5 or 6, but fortunately has a very long-term survival. We know now where the address for that disease is, it is on chromosome 2, and again with the help of agencies like the MDA, we and others are trying to find the specific gene defects.

There has also continued to be dramatic progress in identifying the genetic causes of other types of motor neuron disease. They aren't Lou Gehrig's disease, but they are close enough that we think the lessons we learn from these will help us understand Lou Gehrig's disease. One of them is a devastating infantile-onset disease known as spinal muscular atrophy. There an actual candidate gene has now been identified. Another is an adult-onset ALS look-alike, known as X-linked spinal bulbar muscular atrophy.

What is so interesting in this business is that sometimes the discoveries that are made in pursuit of one disease help you understand others. When Dr. Kurt (Kenneth) Fischbeck (MDA grantee at the University of Pennsylvania in Philadelphia) and others identified a genetic mutation causing this type of motor neuron disease, it turned out in fact to be the same kind of genetic mutation that causes Huntington's disease and several other very important degenerative diseases. So the bigger hope is that if we can all work together and find insight into therapy for ALS, it may in fact have more relevance than just to ALS. It may be relevant to Parkinson's disease or Alzheimer's disease or other related entities.

There is another form of motor neuron disease. It selectively targets motor neurons in the brain. It's called hereditary spastic paraparesis, and I think It's rather extraordinary that there are now six different genetic addresses for defects that cause this disease. As yet the genes are not known, but these six addresses were basically unknown only five years ago. So this really is a major, major step forward and is yet another reason why we can all feel more than cautious optimism that the progress is going to continue in this disease.

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ALS RESEARCH GRANTS FUNDED BY MDA

MDA is the nation's largest nongovernmental sponsor of ALS research. Below, in alphabetical order by state, are listed MDA's current ALS grants, totaling more than $3.2 million.

CALIFORNIA

La Jolla

Burnham Institute - $189,028
Dale E. Bredesen, M.D.
Summary: Studies will be conducted of the mechanism by which ALS begins for the purpose of designing new therapies.

Ludwig Institute for Cancer Research - $28,000
Lucie I. Bruijn, Ph.D.
Summary: The cause(s) of motor neuron degeneration in almost all incidences of (ALS) is unknown. This project will investigate possible causes, which could have important implications on therapeutic intervention in ALS.

San Francisco

California Pacific Medical Center- $48,522
Jane A. Kent-Braun, Ph.D.
Summary: Researchers will investigate the role of poor signal transmission from the brain to the muscle in excessive muscular fatigue of persons with ALS.

University of California - $79,188
David S. Bredt, M.D., Ph.D.
Summary: Researchers will study how nitric oxide, a novel neurotransmitter, and superoxide, a neurotoxin, interact in the development and progression of motor neuron degeneration.

Robert Maiwald, M.D.
Summary: Genetically manipulated mice mimicking familial amyotrophic lateral sclerosis will be developed and tested as possible animal models that would be valuable for evaluating therapies.

COLORADO

Denver

Webb-Waring Institute - $157,625
Richard M. Wright, Ph.D.
Summary: This proposal will characterize the location on chromosome 2 of a second gene, ALS2, that is now linked to amyotrophic lateral sclerosis.

FLORIDA

Miami

University of Miami - $52,500
Scott R. Whittemore, Ph.D.
Summary: Motor neuron cell lines that are relevant to ALS will be developed in order to study the molecular mechanisms causing motor neuron loss.

GEORGIA

Atlanta

Emory University - $55,132
Jeffrey Rosenfeld, M.D., Ph.D.
Summary: Changes in antioxidant proteins such as SOD1 during nerve degeneration in motor neuron disease will be studied.

HAWAII

Honolulu

University of Hawaii - $52,500
Steven Robinow, Ph.D.
Summary: Cells are sometimes inappropriately programmed to die in certain neurodegenerative diseases. The mechanisms that regulate programmed cell death will be studied since they may apply to amyotrophic lateral sclerosis. The project will determine if a factor called EcR-A controls cell death and if EcR-A levels program neuron death.

ILLINOIS

Evanston

Northwestern University - $48,155
Zafar Iqbal, Ph.D.
Summary: The proposal is aimed at determining what causes the reduction in free radical removal from motor neurons that is associated with one form of amyotrophic lateral sclerosis. The information obtained from these studies will be helpful in designing a replacement therapy to improve free radical removal, which is deficient in individuals with ALS.

MARYLAND

Baltimore

Johns Hopkins University - $256,913
Valina L. Dawson, Ph.D.
Summary: The role of free radicals in motor neuron disease will be studied and whether gene therapy of antioxidant gene products can rescue FALS mice from disease will be examined.

Jeffrey D. Rothstein, M.D., Ph.D.
Summary: Glutamate transporters prevent excitotoxicity, a possible cause of ALS. These studies will investigate why there is a loss of glutamate transporters in ALS, and which of the proteins are more important in preventing glutamate toxicity.

MASSACHUSETTS

Boston

Brigham and Women's Hospital - $191,160
Matthias A. Hediger, Ph.D.
Summary: ALS is a highly lethal neurodegenerative disease which affects motor neurons in the spinal cord and motor cortex. The goal of the proposed studies is to elucidate the role of glutamate transporters and reactive oxygen species in the progression of the disease.

Massachusetts General Hospital - $101,297
M. Flint Beal, M.D.
Summary: It's proposed that energy metabolism defects may underlie neuronal death in ALS. Cerebral glucose use in a transgenic mouse model of ALS will be measured, to identify any metabolic changes associated with the onset of motor neuron disease.

Jonathan L. Haines, Ph.D.
Summary: This proposal continues research efforts to find and study the genes that cause ALS, and is designed to answer new questions that arose from previous work.

Charlestown

Massachusetts General Hospital - $155,948
Merit E. Cudkowicz, M.D., M.Sc.
Summary: Mouse models will be used to study the cause and treatment of ALS.

MICHIGAN

Ann Arbor

University of Michigan - $123,904
Eva L. Feldman, M.D., Ph.D.
Summary: The goal of this project is to understand the mechanism which underlies the use of insulin-like growth factor 1 (IGF-1), also known as Myotrophin, in the treatment of ALS.

John K. Fink, M.D.
Summary: Familial spastic paraplegia (FSP) is an inherited spinal cord disease that causes paralysis of the legs. One gene for FSP is on chromosome 15. This project will identify genes from this chromosomal region that could cause this condition. This knowledge will help design treatments for FSP and related disorders, including ALS.

MISSOURI

St. Louis

Washington University - $ 55,125
William D. Snider, M.D.
Summary: The purpose of the study is to determine if different groups of motor neurons have different abilities to defend themselves against oxidants with their own antioxidant defenses. Any differences will be explored as to their association with ALS.

NEW YORK

New York

Columbia University - $282,873
Serge E. Przedborski, M.D., Ph.D.
Summary: Researchers propose to study superoxide dismutase (SOD) and other free radical scavenging enzyme activities, and to determine any biochemical markers that can show free radical tissue damage in ALS.

Carol M. Troy, M.D., Ph.D.
Summary: The aim of this project is to determine how free radicals and oxidative stress produce neuronal degeneration.

Rochester

University of Rochester - $66,150
Denise A. Figlewicz, Ph.D.
Summary: Researchers will develop cell lines in culture that have a copy of the defective superoxide dismutase (SOD1) gene in order to study how defects in this gene lead to the death of motor neurons in ALS.

NORTH CAROLINA

Durham

Duke University - $453,887
Margaret A. Pericak-Vance, Ph.D.
Summary: A collaborative project among four groups located at Duke University, Northwestern University and Massachusetts General Hospital. This project aims to improve diagnostic and therapeutic methods in ALS.

Allen D. Roses, M.D.
Summary: This project aims to understand the mechanisms involved in ALS and nemaline myopathy by studying the protein interactions, in order to identify possible rational therapies.

Winston-Salem

Bowman Gray School of Medicine - $82,017
Osvaldo Delbono, M.D., Ph.D.
Summary: This project will investigate the role of calcium and antibodies in motor neuron death in ALS. The main goal is to define the mechanisms of cell injury and prevent motor neuron death in ALS.

Linxi Li, M.D., Ph.D.
Summary: This project will attempt to establish an animal model for examining the processes of neuronal death in adult mammals following injury and the possible role of trophic factors as therapeutic agents to block these processes.

PENNSYLVANIA

Philadelphia

Children's Hospital of Philadelphia - $310,760
Phillip F. Chance, M.D.
Summary: This project will seek to identify the abnormal gene in a family with a juvenile onset form of ALS.

David E. Pleasure, M.D.
Summary: Using clonal human neurons, we will test if neuronal loss in ALS is caused by calcium overload, free radicals, and damage to mitochondrial and nuclear DNA.

TEXAS

Houston

Baylor College of Medicine - $157,625
Stanley H. Appel, M.D.
Summary: These studies will investigate how antibodies from individuals with ALS can cause changes in the structure and physiology of motor neurons in experimental animals by interacting with calcium channels present at the end of the motor nerve.

Jeffrey L. Noebels, M.D., Ph.D.
Summary: This project will use genetically engineered defects in a gene for the reuptake of the neurotransmitter glutamate to create models of excitotoxic cell death in ALS. These models are critical to understand basic mechanisms of the disease and to develop therapies.

WISCONSIN

Madison

University of Wisconsin - $123,562
Benjamin R. Brooks, M.D.
Summary: The aim of this study is to determine whether reduction of nitric oxide will delay motor neuron degeneration in an animal model of ALS.

ARGENTINA

Buenos Aires Instituto de Investigaciones Neurologicas - $24,516
Osvaldo D. Uchitel, M.D.
Summary: This research will study the pathogenic role of the immunoglobulins in ALS and their effect on motoneuron somatic and nerve terminal calcium channels.

CANADA

Montreal

Montreal General Hospital Research Institute - $110,250
Guy A. Rouleau, M.D., Ph.D.
Summary: The project will generate a series of transgenic mice models that can be used to determine the precise cause of ALS and to test potential treatments. It will also explore the possibility of gene therapy using the adenovirus system as a means of direct gene transfer into the mouse nervous system.

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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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