Motor Neurone Disease - optimist's news

Welcome to the optimists page with details of what I think are good leads in the race to find a cause and cure for Motor Neurone Disease. This page is intented give hope to those of us whose "fuse" is burning away relentlessly.
Here's stuff which I personally found very interesting....

Subject: 8th International Symposium on ALS/MND - some remarks by Ted Heine,USA, and Rolf Busch, Germany.


Dr. Vincent Meininger, France, discussed the present status of clinical trials, including SR57746A, the "Sanofi drug." The rate of enrollment by the end of October was approximately 800 patients in the Rilutek + SR57746A arm, and 300 in the SR57746A or placebo arm. The rate of enrollment is such that closing is expected in February or March. In the Phase I/II trial 110 patients were given 0.5 to 4.0 mg of the drug daily. Healthy controls received 1-35mg/d. The maximum tolerated dose was 2mg/d. A steady state was achieved after 2 months. (I read this to mean that side effects ended after 2 months.) At the end of 32 weeks the rate of decline in vital capacity, and as judged by manual muscle testing was STATISTICALLY SIGNIFICANT!!!!


4. Italian researchers presented the positive results of a gabapentin (Neurontin) trial with 101 patients:

The analysis between pre-treatment and treatment period showed a statistically significant decrease of the decline of muscle strength (P less than 0.001) and Norris score (P less than 0.01) during the treatment period... Survival analysis showed a significant longer survival in treated patients... Our study suggests that gabapentin seems to be an effective drug for ALS. It slows the progression of muscular strength decline and prolongs survival also at low dosages. Further studies with gabapentin alone or combined to riluzole are needed to define the effects of different dosages and duration of treatment."

The highest dose given in this trial was 1 gr/day.

5. Ted Heine reported his own progress under intrathecal BDNF treatment, as he did in this digest # 399: "Possible drug benefits: On July 11 regained bilateral motor control of my toes (suggesting regrowth of axons) which I had not been able to move voluntarily for about two years." I saw him wriggle his toes in Glasgow, and even though Ted himself is very cautious about generalizing his own experience, I think the wriggling of his resurrected toes is a very important event for the ALS community.

The current hypothesis regarding nerve regeneration is more or less: "What is kaputt, is kaputt." or: "Gone is gone." But, as Sir Karl Popper has pointed out, a hypothesis has to be "falsifiable" to be scientific. Take for example the hypothesis: "All swans are white." If you find just one black swan, then this scientific hypothesis has been falsified. Maybe Ted Heine's wriggling toes are the black swan of nerve regeneration? 

Scientists Link Two Genetic Mutations to Deadly : Non-Inherited Muscle Disease
CREDIT: From Times staff and wire reports
DATE : 11/21/96
SOURCE: Los Angeles Times
Johns Hopkins University researchers have identified two genetic mutations that appear to cause or contribute to nearly half the non-inherited cases of the deadly muscle disease amyotrophic lateral sclerosis, better known as Lou Gehrig's disease.

Scientists discovered in 1993 that the inherited form is caused by a defect in a gene called superoxide dismutase 1 that clears toxic wastes from the body.

Dr. Jeffrey Rothstein and his colleagues told a meeting of the Society for Neuroscience in Washington that the defect involves a protein, called EAAT2, that normally deactivates and recycles glutamate, a chemical used by nerve cells to send messages to each other. 

Toxicant exposure and ALS

HAZCHEM ALERT (August 1996)

ENVIRONMENTAL TOXICANT EXPOSURE is related to motoneuron disease; a case study reported amyotrophic lateral sclerosis after occupational exposure to solvents and metals. The article discusses the environmental toxin theory of motoneuron disease, including epidemiological, clinical, and experimental aspects as well as individual susceptibility. In Italian.

(Med Lav 86(6), 522-533 (1995); Chemical Abstracts 1996:272160) 

New drug trial in Boston.

New drug trial is being held in Boston using a drug called procysteine. It is being conducted by Dr. Robert Brown who found the ALS SOD1 gene on chrom 21

Procysteine is acysteine pro-drug that increases intracellular glutathione levels. Glutathione is a potent endogenous antioxidant. 


Reported by MDA in August 1996 "Quest" magazine volume 3 number 3 Researchers at Massachusetts General Hospital in Boston are recruiting patients with familial amyotrophic lateral sclerosis for a trial of the drug penicillamine which is a copper chelator used in Wilson disease and also for rheumathoid arthritis. Apparently it is a very tough drug on your system.

See article below on role of copper / SOD1 in ALS. 

Los Angeles Times Front Page Friday, January 26, 1996

Scientists Find Gene's Trigger in Gehrig's Disease
by Thomas H. Maugh II, Times Medical Writer

UCLA and LA Jolla Cancer Foundation scientists believe they have solved themystery of how a defective gene causes the inherited form of Lou Gehrig's disease, a discovery that is expected to lead swiftly to trials of new experimental therapies for the devastating disorder.

The researchers traced the problem to overactivity of the copper-containing enzyme produced by the defective gene. This overactivity, in turn, leads to the death of nerve cells in the brain and spinal cord that control muscle movement,Dr. Dale E. Bredesen of the cancer foundation and his colleagues report today in the journal Science.

Certain medications -- some already approved by the Food and Drug Administration for other uses -- appear capable of halting this degenerative process by binding to the copper in the enzyme, the scientists said. Researchers are testing the drugs in mice bearing the defective gene and are gearing up to test them in humans if the mouse studies are successful. The disorder, known clinically as amyotrophic lateral sclerosis, or ALS,strikes 30,000 people each year in the United States and there are few effective treatments.

"This is another important step in helping us to understand the pathogeneses of this terrible disease," said Robert Abendroth, chairman of the Research Committee of the ALS Assn. in Woodland Hills. "Dr. Bredesen's answer is particularly significant because of its long-range therapeutic implications." "The most important thing we need to gain is an understanding of the relationship of the [mutant] gene to the disease itself," said Donald S. Wood,director of science technology for the Muscular Dystrophy Assn. Bredesen's discovery "doesn't yet answer that question definitively . . . but it does giveus a sense that we are on the right track. If solid evidence comes up to support his conclusions, then we'll see some real excitement" ALS strikes about one in every 10O,000 people worldwide. The ALS-triggered nerve cell death produces muscle weakness and paralysis. Most ALS victims die within two years after the disorder's onset but some live much longer. ALS occurs in two forms. Hereditary or familial ALS, in which a defective gene is passed down through a family accounts for about 10% of cases. The sporadic form, which does not run in families and whose cause is unknown accounts for the remaining 9O%.

About three years ago, researchers discovered that the familial form of the disease is caused by a mutation in the gene that is the blueprint for a protein called superoxide dismutase, or SOD1. The same gene that causes the familial form is now known to be responsible for at least a quarter of the sporadic cases.

SOD1 is an enzyme that clears certain types of toxic wastes, called superoxides, from the body. Researchers immediately assumed that the mutant gene could no longer do this, and that the accumulation of superoxides caused the death of neurons characteristic of ALS. Two years of intensive research in several laboratories showed that this isnot the case. Instead, it has become clear that the mutant gene has picked up adeadly new function.

Bredesen and chemist Joan S. Valentine of UCLA knew that SOD1 had a secondary, less desirable activity -- adding oxygen to molecules in the cell,causing the molecules to break down. In healthy people, this so-called peroxidase function is outweighed by the benefits of the destruction ofsuperoxides.

When the team studied this secondary effect in cells containing the mutant enzyme, Bredesen said, "Lo and behold, [the peroxidase activity] was increased dramatically." They then tried blocking the activity. Since SOD1 only works in the presence of atoms of copper, the researchers tied up copper atoms with so-called chelaling agents. These drugs, which are used to treat accidental copper poisoning from industrial or household chemicals, reduced the death of cells containing the mutant gene by 30% to 70%. Moreover, they had no effect on cells containing normal SOD1.

At least two laboratories are testing the chelators in mice that have mutant SOD1 and develop ALS, Bredesen said, "If these tests are successful, we'll see clinical trials in humans fairly soon." But he cautioned that the chelating agents can be toxic in high doses, and warned against doctors prescribing them before tests are completed "I would be very, very cautious about suggesting to anybody that they go out and buy these things." Although the new research so far applies only to the familial form of ALS,experts are optimistic that it will eventually provide insight into the sporadic form as well. "Pathologically, the sporadic and familial forms are identical," said Bredesen.

The one drug approved for treating ALS, riluzole, equally helps people withboth types of the disease he noted. "In all likelihood, there is a common biochemical pathway between the twoforms, even they have a slightly different cause. A new treatment that worksfor one form, scientists reason, may work for the other. "People are fairly optimistic," Wood added, "that if we continue to pursue research here, we're going to get answers to a lot more than just the familialcases ALS."

Regeneron Scientists Identify Nerve-Muscle Communication Key

Will it come in time for ALS victims?

TARRYTOWN, N.Y. (Dow Jones)--Regeneron Pharmaceuticals Inc. (REGN) scientists have identified the naturally occuring ligand, called Agrin, that activates a muscle-specific growth factor receptor. In a press release, Regeneron said the scientists have discovered that activation of a muscle-specific growth factor receptor, which the scientists previously cloned and named MuSK, is responsible for triggering all aspects of neuromuscular junction formation. The company said the neuromuscular junction, located at the nerve tip where it contacts the muscle surface, is the connection point at which communications between nerve and muscle take place. Regeneron said this research will be published in two articles in the scientific journal ''Cell.'' A company spokesman said human agrin has now been cloned and work is underway to develop a manufactured version of agrin. The discovery raises the possibility of using drugs to stimulate the MuSK receptor, which would then activate muscle growth. Regeneron said this could help maintain muscles that are at risk of atrophy and degeneration from muscular dystrophies, motor neuron disease (ALS) or broken bones that are in casts. (END) DOW JONES NEWS 05-17-96 

BOSTON (AP) -- Scientists have unraveled the mysteries of one of life's most basic pieces of wiring -- the connection between nerves and muscles. Every time someone twitches a toe or wiggles a finger, the nerves communicate with the muscles. But just how the body constructs the biological machinery that makes this happen, usually flawlessly, has been unclear. "This is the most intensively studied communications relay point in the human body," said Dr. George Yancopoulos. "Understanding it is a Holy Grail." Now Yancopoulos and another team, working independently, have produced three reports published Thursday that provide the most detailed picture yet of this incredibly complex system. The discovery may offer clues about how cell-to-cell communication goes on inside the brain, and it could also lead to new treatments for nerve injuries and a variety of diseases such as myasthenia gravis that occur when these cell connections become garbled.

Further, the research may yield a remedy for muscle atrophy that occurs when people break bones or become bedridden. Nerve cells talk to each other, as well as give orders to muscles, by sending messages across gaps called synapses. The new work shows how these synapses are formed where nerve meets muscle, a point called the neuromuscular junction. "If cells connected to each other willy nilly, they would work about as well as a radio if the wires were soldered at random," said Dr. Joshua R. Sanes of Washington University in St. Louis, another of the researchers. Instead, nerves and muscles create chemically intricate synapses in just the right places. The secret, it turns out, seems to be two proteins -- one called agrin and another known as muscle-specific-receptor kinase, or MuSK.

Sanes and colleagues looked at the role of agrin, while Yancopoulos and others from Regeneron Pharmaceuticals Inc. of Tarrytown, N.Y. examined agrin's interaction with MuSK. Their reports were published in the journal Cell. Both worked with mice that were missing the genes that produce agrin or MuSK. They found that both proteins are necessary during embryonic development to make working connections between nerves and muscles. If either is missing, the effect is the same: The mice are unable to move or breathe and die shortly after birth.

A major problem in treating nerve injuries is getting the nerves to grow back and work properly. Dr. Zack W. Hall, director of the National Institute of Neurological Disorders and Stroke, said the latest studies bring scientists a step closer to solving this. "The problem with regeneration is trying to recreate those embryonic conditions in which they were formed in the first place. The more we know about this, the better we can encourage that regeneration," he said. During development, it now appears that nerve cells grow toward muscles and then release agrin. On the muscle side of the gap, the agrin is received by MuSK, which works in combination with another protein called muscle-associated specificity component, or MASC. This triggers a complicated chain reaction that eventually results in changes in both the nerve and the muscle that add up to a working synapse.

When this system is up and running, the nerve cells talk to the muscle cells by sending a chemical code in the form of the neurotransmitter acetylcholine. Agrin is the first step. It signals the muscle to pull together the chemicals it needs to construct acetylcholine receptors so it can receive these messages. Regeneron scientists say agrin works like a muscle growth hormone, and it might be used as a medicine for some muscle conditions. When people break bones and have to be immobilized, their muscle quickly begins to atrophy. The Regeneron researchers have produced the human form of agrin and are testing whether it can halt this muscle breakdown. 


INVESTEXT/BIOTECHNOLOGY (Thursday June 20, 1996)


< most of this massive report has been deleted >

Neurobiological Technologies, Inc. (NTI) is a biopharmaceutical company headquartered in Richmond, California. The company's strategy is to focus on acquiring products, primarily through its network of scientists, that are neuroscience-based with novel pharmacological activity and a clear clinical development path. Using a strategy of licensing in products for clinical development and outsourcing its manufacturing and clinical trials, this "virtual" paradigm has so far been successfully implemented by the company, in that its lead three products, CRF, Dynorphin A and Memantine have entered into advanced clinical development. Since its inception, the company to date has spent over $17 million for the clinical development of its three lead products.

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The company's third leading and probably most intriguing product is memantine. The drug has been used in Germany for the last twelve years in treating patients with Parkinson's disease. It was only recently discovered by Stuart Lipton, M.D., Ph.D., in the Department of Neurology at the Harvard Medical School, that memantine's mechanism of action in the central nervous system was that of an open ion channel blocker associated with the NMDA receptor.

The NMDA receptor regulates the voltage-gated influx of positive charged ions (cations) such as calcium into neurons. An influx of cations into neurons depolarizes its surface membrane, giving rise to a wave of an electrical impulse along the nerve fibers. Glutamate is an excitatory amino acid (EAA) which functions as a neurotransmitter that binds to the NMDA receptor in the brain. Glutamate is responsible for brain-controlled activities such as memory, sensation, cognition and movement through its interaction and activation of its specific membrane receptors. Excessive activation of glutamate receptors has been coined as "excitotoxicity" in which an excessive influx of calcium into neurons can lead to neuronal injury and death. Many neurologic conditions, both acute and chronic, appear to converge on a common pathway where overstimulation of receptors for excitatory amino acids give rise to diverse neuropathophysiological conditions

(Lipton, S.A. & Rosenberg, P.A. Excitatory amino acids as a final common pathway for neurologic disorders. New Eng. J. Med. 1994; 330: 613-622).

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Memantine's fast kinetic rate to block and unblock the calcium channel in micromolar concentrations gives the drug the unique property of being an orally safe and effective neuroprotectant to excitotoxicity and subsequent neuronal injury. Memantine's properties make it an ideal drug candidate to treat both acute (head trauma, epilepsy and stroke) and chronic (Alzheimer's and Huntington's diseases, amyotrophic lateral sclerosis, neuropathic pain and AIDS-related dementia complex) neurologic conditions.

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The initial clinical indication the company will pursue for memantine is AIDS-related dementia complex. Cognitive and motor disorder in HIV-infected patients is believed to be a chronic neurodegenerative disease caused by over-stimulation of the NMDA receptor through cytokines produced from viral- infected mononuclear phagocytic cells.

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Selecting AIDS-related dementia for memantine, as the first clinical indication over trauma or stroke, reflects NTI's opportunistic strategy to license in products that can be simply manufactured with a clearly defined late stage clinical development path. This indication puts memantine on a potential fast track, expedited FDA review process, while at the same time demonstrating proof of concept that memantine is an effective oral neuro- protectant. 

Study Previewed at Houston Conference Provides New Interpertation on How Chronic Diseases Progress
Findings Suggest Link Between Retrotransposons, Chronic Inflammation and Disease Advancement

You can locate the entire article plus more from:

Entire Article

Houston, Texas -- April 12, 1996 -- Speaking to the 8th Annual Houston Conference on AIDS in America, Dr. Howard B. Urnovitz, Chief Science Officer for Calypte Biomedical, previewed the findings of a new study investigating the underlying mechanisms in the progression of HIV-infected patients to AIDS. The data, to be presented next month at the American Society of Microbiology, suggest that the presence of antibodies to retrotransposons may provide a window into the advancement of chronic diseases.

Retrotransposons, or HERVs, are normal genes found in all animals. The detection of antibodies to these normal genes signals an underlying breakdown of the heavily-regulated immune system, a critical event known to allow HIV-1 infection to culminate in AIDS. Using a specially-designed investigational diagnostic test, researchers were able to measure each subject's retrotransposon antibody level and correlate it with CD4 count and HIV virus load. The findings suggest that researchers may be able to track the progression of HIV infection to AIDS through monitoring retrotransposon antibodies.

"The presence of retrotransposon antibodies may serve as a warning sign that an underlying persistent inflammation may be occurring. It is similiar to a wound that will not heal," said Dr. Urnovitz.

Urnovitz went on to describe the role retrotransposons also may play in other chronic diseases such as Chronic Fatigue Syndrome, Persian Gulf War Syndrome, cancer, neurologic disorders and autoimmune diseases. He discussed his current research efforts, which have shown that retrotransposons may play a role in "archiving" virus fragments as a way of creating "molecular memory."

Urnovitz used post-polio syndrome as an example of how retrotransposons may work. The majority of the 1.63 million Americans who had polio 20 to 40 years ago now suffer from a variety of illnesses described as post-polio syndrome. According to the scientific literature, post-polio syndrome patients have fragments of the polio virus left behind in their nerve tissue. Retrotransposons may have copied these fragments into memory in the form of host DNA (the patient's own DNA). Although these fragments normally remain benign, an outside "opportunistic" infection or chemical agent may inflame the tissue to produce the virus fragments, igniting the symptoms physicians now refer to as post-polio syndrome -- central nervous system disorders, muscle fatigue and joint pain, for example. These types of illnesses have been seen in over a dozen epidemics in the last 60 years. "The result of continually expressed archived fragments is the presence of white blood cells in tissues. These white blood cells may interfer with cellular and tissue activities thus leading to symptoms such as fatigue."

What may be the source of other "archived" viral fragments in so many people. Urnovitz went on to describe how polio vaccines (given between 1955 and 1961 in the U.S.) contained low levels of live monkey viruses. "As is commonly known, Americans were given 'inactivated' polio vaccines that actually contained up to 26 contaminating monkey viruses.

The viruses were unknowingly introduced into the vaccine because the polio virus was grown in contaminated monkey kidney cells. Many of the new syndromes have some association with the possible contaminants in the vaccine," said Dr. Urnovitz. 

Subject: Vitamin E Therapy Successful?

In July 1994 the physician Dr. Carsten Hager published a case report of an apparently rather successful treatment of ALS with high doses of vitamin E in a regional German medical paper: "Therapieversuch der amyotrophen Lateralsklerose (ALS). Der besondere Fall." (A Therapy Trial of Amyotrophic Lateral Sclerosis (ALS). A Special Case.) Schleswig-Holsteinisches Aerzteblatt 7/94, pp.5-6.

The patient was treated with 5000 IU of vitamin E per day. (His mother had died of ALS. And he had had polyiomyelitis at the age of six.) Before treatment he was exhausted after walking for about 200 meters. He could scarcely mount steps. After about 6 months of treatment he enjoyed taking walks of 4 kilometers every day, he mounted steps without problems. No adverse effects. The atrophy of hand muscles had not improved, but there had been no more progression of disease either. Dr. Hager was very cautious about his results, he wrote: "I am reporting this case to help other patients, who may want to try the described therapy, as long as no cure for ALS has been found."

I had a telephone call with Dr. Hager in spring 1995 and he told me that he was the described patient himself. He was happily working in his garden.A few weeks ago I rang him up again, and again he had to be called in from working in his garden to come to the phone. He was quite optimistic and felt the same as more than a year ago. After his publication many people from all over the world had asked him about his therapy and he had tried to keep in contact with them to find out, what their experience was. I asked him to write a short paper about these experiences, perhaps to be published in the ALS DIGEST. Here is a shortened version of his paper, which I translated into English:

"After my publication in July 1994 I had 112 inquiries from patients and doctors. 88 of these patients began a vitamin E therapy after that. 24 did not want to begin a therapy, mostly because of a too advanced stage of the disease. 14 patients died during therapy having only been able to take vitamin E for a few weeks. The dose taken is 5000 mg per day.

I questioned every patient after 6-8 months of therapy. My evaluation is based on 46 answers. 9 did not answer, 19 did not take vitamin E long enough. The following conclusions can be drawn at the present moment:

1) No patient experienced any adverse effects with the high dosis.

2) After approximately 3 months of therapy all patients had better appetite, increase in weight and consequently a definitely improved mood.

3) Many doctors point to completely normal blood values, some pathological values normalised.

Out of the cases evaluated so far 9 came to a standstill, 5 of these with a slight or temporary improvement.

Here are 5 examples:

1) The first case published 7/94. Unchanged since then. The disease started 6 years ago, vitamin E has been taken for 3 (!) years now. (I am this patient myself.)

2) The patient was unable to speak. After 6 months of therapy she could speak again. (As documented by her neurologist.) Yet after 15 months she developped a quickly deteriorating periphery palsy.

3) This patient was entirely dependent on artificial ventilation. After 8 months of therapy artificial ventilation had only to be used from time to time. Yet here also a quickly progredient periphery palsy after 12 months. Death.

4) At the beginning of therapy the patient was wheel-chair-bound. After continuous progression of disease there is a complete standstill now since about one year. The patient has just flown to spend a holiday on Crete (with a companion).

5) An ALS patient with progredient periphery deficiencies. No more deterioration since about a year. The patient started working in his garden again.

It is important to be aware, that in all these 9 cases improvement became apparent only after 6-8 months of vitamin E therapy. All patients practised30 minutes of physical therapy twice a day.

Let me finally point to two recently published articles:

1) Protection against myocardial infarction by vitamin E. Success after 200 days of therapy! (See CHAOS-trial Nigel Stephens, Papworth Hospital, Cambridge.)

2) A trial with transgenic mice showed that vitamin E could retard the outbreak of ALS and slow progression. (ME Gurney; Ann.Neurol.1996,39: 147-157)

The author's address: Hager, Suelzberg 6, D23843 Bad Oldesloe, Germany. Tel. 04531/81555."

Support for Irish MND sufferers and their families can be got from.

The Irish Motor Neurone Disease Association based at

Carmichael House,
North Brunswick Street,
Dublin 7,


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