This year saw the start or continuation of many clinical trials of possible treatments for MDA-covered diseases. Some of the most exciting are the neurotrophic factor trials and anti-glutamate drugs in amyotrophic lateral sclerosis (ALS), and the deflazacort trial in Duchenne muscular dystrophy.

WHAT IS MDA'S ROLE?

MDA usually doesn't get directly involved in drug development. The Association funds basic science research in muscle and nerve problems that often leads pharmaceutical and biotechnology companies to develop drugs or other potential treatments. The companies usually come back to MDA to use its clinics to test drugs in people with neuromuscular diseases. MDA sometimes provides direct funding to help with drug or other treatment trials.

FIND OUT ABOUT TRIALS

The best way to find out which trials are still open and whether you or a family member qualifies for a trial is to keep in touch with your MDA clinic director, who receives regular communications from MDA's Research Department regarding open trials. Clinic directors also receive communications from pharmaceutical companies looking for patients for trials.

Some of the trials listed below are organized by companies that welcome calls. The phone numbers given were supplied by these companies.

ANTIOXIDANTS FOR ALS

The rationale for using antioxidants in ALS is the finding by MDA-funded researchers in 1993 that a defect in a gene for the antioxidant SOD1 can cause ALS. Although most people with ALS don't have this gene flaw, doctors suspect that a lack of antioxidant activity may underlie ALS even in cases where no gene flaw exists.

Trials of antioxidant therapy using oral substances other than SOD1 are under way at Massachusetts General Hospital in Boston. No recoveries have been seen, but no adverse effects have been noted either. Patients take the vitamins at home and are checked every four weeks.

A trial of SOD1 itself, delivered directly into the spinal fluid, is under way at Boston's New England Medical Center. SOD1 is destroyed in the digestive system, so it can't be given orally. Researchers believe that, if SOD1 is beneficial, it will do the most good if injected near the neurons of the brain and spinal cord, the cells that die in ALS.

NEUROTROPHIC FACTORS FOR ALS

Neurotrophic factors are natural substances that promote and sustain the growth of nerve cells. MDA scientists have been studying them for many years and have identified a few that have potential for treating ALS. Several pharmaceutical companies have designed trials to test these factors.

In June, two pharmaceutical companies announced that their joint trial of brain-derived neurotrophic factor (BDNF) in ALS slowed the deterioration in breathing capacity in that disease. The companies are Amgen (Thousand Oaks, Calif.) and Regeneron (Tarrytown, N.Y.).

The companies now plan to expand testing of BDNF, studying about 1,000 patients in 39 centers in the United States and Canada. The large trial will use subcutaneous (under the skin) administration. Call Amgen at (800) 772-6436.

One trial of ciliary neurotrophic factor (CNTF) was stopped in 1994 and another early this year when toxic side effects and lack of therapeutic effects were found. The drug was being given subcutaneously in both trials.

A new approach is being taken by CytoTherapeutics of Providence, R.I., which has developed a method for delivering CNTF into the spinal fluid. Ten people with ALS are in a trial in Lausanne, Switzerland, using a unique delivery method. Hamster kidney cells have been genetically engineered to produce a continuous supply of CNTF and so as not to attract the attention of the immune system. So far, no adverse effects have been found.

The drug company Cephalon (West Chester, Pa.) is betting on insulin-like growth factor 1 (IGF-1), given the trade name Myotrophin. In June, Cephalon announced that people with ALS who received Myotrophin subcutaneously experienced less disease severity, slower progression of disease and better functional ability compared to those who got a placebo. Cephalon is seeking Food and Drug Administration approval for Myotrophin. If you were in a Myotrophin trial, you can now get the drug as long as supplies last. Call the company at (800) 797-0705 for more information.

ANTI-GLUTAMATE DRUGS AND ALS

Glutamate, a natural central nervous system chemical that normally transmits nerve signals from cell to cell, has been under scrutiny by MDA-backed scientists for several years. Recently, MDA research has led to the theory that, in ALS, something goes wrong with glutamate. One popular guess is that, in at least some people with the disease, glutamate isn't cleared away from cells as quickly as it should be, leading to a toxic buildup of the substance.

Gabapentin (trade name Neurontin) is a drug already being used for epilepsy that seems to have anti-glutamate activity or to protect cells from excess glutamate. It's now being tested at seven medical centers under the auspices of its manufacturer, Parke-Davis (Morris Plains, N.J.). Results are expected this spring or summer.

Another anti-glutamate drug, riluzole (Rilutek), has been tested by the international pharmaceutical company Rhone-Poulenc Rorer (Paris, France, and Collegeville, Pa.). Based on clinical trial results, the FDA announced in June that RPR can begin an early access program for people with ALS in the United States, pending final approval of Rilutek for ALS. In September, an FDA advisory committee recommended approval of this drug for ALS. If approved, riluzole could be in pharmacies by the end of the year. Call RPR at (800) 798-7425.

STEROIDS FOR DUCHENNE

Studies since the 1970s have suggested that the steroid drug prednisone may be helpful in slowing the course of muscle degeneration in Duchenne dystrophy. Doctors have theorized that treatment with steroids might preserve muscle that could then be treated with a more curative therapy later.

But prednisone has many bad side effects weight gain, bone and skin deterioration, cataracts, high blood pressure, fluid retention and psychological difficulties, to name a few. Many children can't or don't want to tolerate prednisone for very long, so doctors are hoping to find a less toxic alternative to prednisone that has the same benefit. Uncovering how prednisone works is part of the quest for such an alternative, which might be another steroid or another class of drug entirely.

MDA grantees Robert Griggs at the University of Rochester (N.Y.) and Michael Hudecki at the State University of New York at Buffalo are studying how prednisone works in Duchenne dystrophy. They'll be looking at how prednisone may affect protein manufacture, muscle breakdown and the activities of mast cells, which take part in inflammatory reactions. Twenty boys with Duchenne dystrophy will get either prednisone or placebo for three months and will have muscle biopsies and muscle function tests done.

A multicenter research group coordinated at Vanderbilt University (Nashville, Tenn.) is testing a new steroid, deflazacort, developed by the drug company Marion Merrell Dow (Kansas City, Mo.). Deflazacort was designed to have fewer side effects than prednisone, and tests of the drug for diseases other than Duchenne dystrophy suggest that it does. Preliminary analysis of the Duchenne trial shows deflazacort is just as effective as prednisone. Analysis of the side effects hasn't been completed. Results of the trial are expected in March, 1996.

MYOBLAST TRANSFER FOR DUCHENNE

Myoblasts are immature muscle cells that form muscle fibers during human and animal development and can repair muscle that is injured or attacked by disease.

In 1990, MDA began clinical trials to test whether myoblasts transplanted from healthy fathers or brothers of boys with Duchenne dystrophy would merge with the boys' degenerating muscle fibers and give them new genes for dystrophin, the protein that's missing or ineffective in this disease.

Mouse studies looked promising, but clinical trials have been uniformly disappointing. The last two myoblast transfer trials, one at Ohio State University in Columbus and the other at California Pacific Medical Center in San Francisco, concluded this year with negative results, as did a small trial in Italy.

The Ohio State researchers injected donated myoblasts once a month for six months into one arm and gave a placebo (inactive substance) injection once a month for six months into the other arm in 12 boys ages 5 to 9 with Duchenne dystrophy. Only one child showed a significant amount of dystrophin in the injected muscle fibers (10 percent of his fibers had the protein), but no child showed any improvement in muscle strength.

The California Pacific researchers studied younger boys, ages 2 to 5, and also found no benefit from donated myoblasts. Final analysis of this trial is expected this spring.

A myoblast transfer trial conducted at the C. Besta National Neurological Institute in Milan, Italy, reported its negative myoblast transfer results in July. They studied boys ages 6 to 9.

Researchers haven't given up on myoblast transfer, but nearly all believe more studies in animals need to be done before further human trials are attempted. The main problems are rejection of the transplanted myoblasts by the immune system, early death of the transplanted cells and limited fusion of the cells with the patients' muscle fibers. Also, delivering the myoblasts by a more efficient method than intramuscular injection would be important if the technique were ever seriously considered as a treatment. MDA researchers are now addressing these problems in animal studies.

OTHER CLINICAL TRIALS

The following are clinical trials in progress at press time. They're listed by disease category.

ALS

Ataxias

Mitochondrial Myopathy

Periodic Paralysis

Spinal Muscular Atrophy