The last few years have been exciting ones for MDA's research program, and they've resulted in an unprecedented number of trials to test potential drugs and biological substances in people with neuromuscular diseases.

Let's look at some of the major themes in MDA's current research program, most of which are or soon will be reflected in clinical trials. (For a list of open clinical trials, see the next part of this article. Call the numbers provided for information about enrollment.)

Amyotrophic Lateral Sclerosis

ALS (Lou Gehrig's disease) is a devastating disorder of adults in which muscle-controlling nerve cells known as motor neurons die, causing paralysis and ultimately death. Research in ALS has emerged over the last few years along three main themes. Those themes might be called neurotrophic factors, glutamate inhibition and energy production therapies.

Neurotrophic factors. These are molecules present in the nervous systems of animals and humans that, at least in laboratory situations, appear to protect nerve cells and generally help them grow and thrive.

Unfortunately, neurotrophic factor clinical research has seen some recent disappointments. In April, the pharmaceutical company Amgen announced it would stop a clinical trial to test the neurotrophic factor GDNF in ALS when no benefit was shown.

Then, in December, after several years of trying to obtain marketing approval through the Food and Drug Administration for its neurotrophic factor Myotrophin (derived from the natural factor IGF-1), the drug company Cephalon announced it would discontinue distributing the drug as of Dec. 31. Myotrophin had been available free to a limited number of randomly selected patients. The drug never met the FDA's criteria for effectiveness in ALS.

However, the neurotrophic factor BDNF is being tested by two partner companies, Amgen and Regeneron. These companies are conducting two clinical trials, delivering BDNF to people with ALS via the spinal fluid in one trial and under the skin in another.

Yet another drug, designed to boost the body's production of its own neurotrophic factors, is in clinical trials through Sanofi, a French pharmaceutical firm, with results expected by summer. This drug has only a number to identify it — SR57746A.

Glutamate inhibition. Another major theme in ALS clinical research is interference with the natural nervous system chemical glutamate. Glutamate is a chemical "neurotransmitter," carrying signals among nerve cells in the brain and between nerve cells in the brain and spinal cord. It's a needed chemical, without which paralysis would occur, but too much of it seems to be too much of a good thing.

In ALS, many researchers theorize, there's a problem with too much glutamate reaching motor neurons and possibly other cells as well. There may be a problem with the way in which excess glutamate is removed once it's done its job of carrying signals, or a problem with the way glutamate is received and handled by the cells that are its targets, researchers say.

The only drug now marketed for the treatment of ALS in the United States is riluzole (Rilutek), a glutamate inhibitor originally developed by the pharmaceutical company Rhöone-Poulenc Rorer, which recently became Aventis Pharma AG. This drug is moderately effective in ALS, and much clinical research is aimed at better glutamate inhibition.

Riluzole works by interfering with the release of glutamate from the transmitting cells. It may also have actions that interfere with events in the targeted cells after glutamate has reached them.

Clinical research has expanded on this theme by examining the effects of other methods for inhibiting glutamate or its effects.

Gabapentin (Neurontin), a drug marketed for epilepsy by the Parke-Davis division of Warner-Lambert, was a hoped-for glutamate inhibitor whose mechanism still isn't well understood. It's structurally related to a neurotransmitter that has actions that oppose glutamate, but no one has proven that gabapentin actually performs those actions in the human body. Unfortunately, earlier this year, a large clinical trial found no benefit of gabapentin in ALS.

Now researchers will look at yet another epilepsy drug, topiramate (Topamax), marketed by Ortho-McNeil. This drug may block some of the glutamate "docking sites" (receptors) on cells that normally receive glutamate. A trial of topiramate, with support from MDA, is now under way.

Trials of the dietary supplement creatine in ALS are based on findings by M. Flint Beal of Cornell Medical College in New York.

Other ideas, still on the drawing board, include harnessing the immune system to attack docking sites for glutamate on target cells, and inserting into the nervous system genes for "glutamate transporter" proteins. Glutamate transporter proteins are natural body chemicals that whisk glutamate away from the targeted cells after the necessary chemical transmission has taken place but before the targeted cells are "overexposed" to glutamate.

Energy production. With the exception of a small number of ALS cases in which there is a clear genetic cause, the exact mechanisms underlying the death of motor neurons in ALS remain largely unknown. However, one thing is clear: Motor neurons (and possibly other neurons) die in this disease. So, reason many experts, even without a complete understanding of what's killing the cells, shoring up their defenses is a good idea.

With that theme in mind, MDA is supporting a new, multicenter trial of creatine, a compound involved in cellular energy production that may help motor neurons hold on in the face of whatever may be attacking them. In recent studies, mice with ALS lived slightly longer if given creatine.

A small study of another dietary supplement, coenzyme Q10, is also being conducted. Coenzyme Q10 is also involved with energy production in cells.

Autoimmune Disorders

Most of MDA's disorders are related to genetic flaws, but some — myasthenia gravis, Lambert-Eaton syndrome, polymyositis and dermatomyositis — stem from a different kind of problem. These diseases are known as autoimmune, and they result from a mistake in the body's immune system so that it attacks its own tissues.

In MDA's autoimmune disorders, the target of the immune system's attack is muscle tissue, nerve tissue that sends signals to muscles, or sometimes blood vessels around muscle cells.

J. Edwin Blalock of the University of Alabama at Birmingham is developing vaccines that could fight MG.

Etanercept for dermatomyositis. In a new clinical trial, MDA researchers are studying the use of etanercept (Enbrel) in dermatomyositis. Etanercept is a drug developed for rheumatoid arthritis by Immunex and Wyeth-Ayerst Pharmaceuticals.

The drug blocks tumor necrosis factor, a natural body chemical involved in inflammation. In dermatomyositis, the immune system causes inflammation around muscle cells and the blood vessels in muscles. Current treatments involve global suppression of the immune system and can be highly toxic.

Disarming an immune response by preventing a "second signal." MDA-supported researchers are attempting to treat the autoimmune disease myasthenia gravis (MG) by "disarming" activated T cells, key players in the immune response. If T cells see their targets (in this case, bits of muscle cells called acetylcholine receptor proteins) displayed on cells that line the nasal passages, they apparently lose their ability to go into battle. The strategy has shown promise in rats. (See "MG Nasal Spray Works in Rats," Quest, vol. 6, no. 6.)

Vaccines against an immune response. In a different approach to treating MG, other MDA-supported investigators have developed two "vaccines" that show promise in rats. The vaccines appear to turn the immune system's weaponry against its own mistakes. These vaccines, which also have potential for the treatment of other autoimmune disorders, block only those T cells, B cells and proteins that are involved in an unwanted immune response. (See "Vaccines May Someday Treat MG.")

Muscular Dystrophies

In muscular dystrophies, abnormalities in genes lead to the loss of muscle proteins and degeneration of muscles. Some potential therapies for muscular dystrophies aim to replace the needed proteins by inserting functional genes for the missing proteins or their chemical relatives. Other ideas include teaching cells to "re-read" flawed genes and make a needed protein, inserting whole cells from donors or genetically corrected whole cells from patients themselves, and increasing energy production and tissue preservation in muscle cells.

Gene therapy. The insertion of new genes into cells is known as gene therapy or gene transfer. Most gene transfers are accomplished by first inserting the desired gene into a modified virus and then injecting the virus into the body. MDA is sponsoring a small trial to test the safety of gene therapy in the four forms of limb-girdle muscular dystrophy (LGMD) caused by defects in sarcoglycan proteins. These proteins normally line up in the muscle cell membrane, which protects the cell from stress during contractions.

Results are expected later this year. If the procedure proves to be safe and there is evidence that gene transfer has occurred, the trial will likely expand.

Gene therapy for Duchenne muscular dystrophy (DMD) has been set back by scientific obstacles but is now moving forward again.

The gene that, when flawed, leads to DMD is the dystrophin gene, and it's among the largest genes known. (It's also thought to play a role in protecting muscle cells from the stress of contractions and may also serve other purposes.) To insert such a large gene into muscle cells, a large transporter is necessary.

So far, most experts working with the dystrophin gene have been working with a highly modified form of a respiratory virus known as the adenovirus. But concerns about toxicity of the adenovirus have slowed this field.

Now, MDA researchers are working on at least three new ideas: modifying the adenovirus still further, so that it's much less likely to cause problems; breaking the large dystrophin gene in half, putting each half into two smaller, safer viral transporters, and then making sure the two halves link up; and using another large virus to enclose the entire dystrophin gene.

Gene therapies for many other muscle diseases, including metabolic muscle disorders, in which proteins that play key metabolic roles are missing, are also on the drawing board.

In addition to inserting a specific protein, some scientists are suggesting the insertion of genes that in general add to muscle bulk or preserve muscle tissue that's degenerating because of a genetic flaw. The gene for the protein IGF-1 is a candidate for gene transfer in the future.

Gene re-reading. Studies in mice suggest that an antibiotic, gentamicin, can cause the cells of mice with DMD to "read through" a genetic error in their DNA and begin making dystrophin, the protein missing in the disorder.

This year, MDA is sponsoring a pilot study to see whether children with DMD who have a particular type of genetic mutation — called a premature stop codon — can be helped by gentamicin.

Recruitment for this study is complete, but the researchers are willing to test children for premature stop codons if they have been previously tested and found not to have the more common type of DMD genetic defect, a DNA deletion.

Louis Kunkel of Children's Hospital of Boston found that stem cells taken from mouse muscles or bone marrow can rebuild muscle tissue in mice with a Duchenne-like muscular dystrophy

If gentamicin is helpful in the pilot study, the trial will likely expand to include children found to have a premature stop codon in the dystrophin gene.

Increasing production of related proteins. The dystrophin protein has a close chemical cousin in the protein utrophin, also present in muscle and playing a role similar to that of dystrophin. MDA-funded researchers report they've recently uncovered a better way to "turn on" the utrophin gene than the method they'd previously been using (see "Progress in Utrophin Therapy").

If such a strategy succeeds in animals, clinical trials to test increasing production of utrophin are a possibility.

Energy production and muscle building. Creatine, also being tried in ALS, is being tested to see if it can increase muscle energy production and storage and, thereby, preserve muscle cells or increase strength in DMD.

In one study, glutamine, another dietary supplement, is being combined with creatine. Glutamine is used by body builders and is reputed to help those with muscle injuries to maintain or build muscle tissue.

Two other drugs, albuterol (sustained-release tablets) and oxandrolone (Oxandrin), are also being tested in muscular dystrophy for their possible anabolic (muscle-building) effects. Albuterol has been shown to have anabolic effects on muscles in a pilot study of people with facioscapulohumeral muscular dystrophy, and MDA-supported researchers hope to have results in April.

Oxandrolone is derived from male hormones and has also shown promise for its anabolic effects in a pilot study of boys with DMD. A larger MDA-supported study of 50 boys is now complete and is being analyzed.

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