FDA PANEL SAYS NO ON ALS DRUG MYOTROPHIN

An expert panel convened by the U.S. Food and Drug Administration on May 8 denied an application to market Myotrophin, an experimental treatment for amyotrophic lateral sclerosis (ALS). The drug, also known as insulin-like growth factor 1, is a neurotrophic factor, one of a class of substances researchers believe may help preserve muscle-controlling nerve cells.

The drug companies, Cephalon of West Chester, Pa., and Chiron of Emeryville, Calif., weren't able to satisfy the FDA's standard requirement of two clinical trials showing safety and effectiveness. The drug companies showed safety and effectiveness for Myotrophin in a North American clinical trial, but their European trial showed no effectiveness and even raised questions about safety. Six of the eight North American trial sites are MDA clinics.

The expert panel's decision isn't binding on the FDA, but the agency usually follows its recommendation.

MDA GRANTEE TO TEST IVIG IN MG

Richard Barohn, MDA clinic director at the University of Texas Southwestern Medical Center in Dallas, has MDA funding to do a clinical trial of intravenous immunoglobulins (IVIg) in myasthenia gravis. MG is an autoimmune disease involving fluctuating weakness due to faulty nerve-to-muscle communication. In autoimmune diseases, a person's immune system mistakenly attacks some of his own tissues with antibodies (also called immunoglobulins), immune-system proteins that normally attack bacteria, viruses and other foreign invaders.

In MG, there are drug therapies, such as pyridostigmine (Mestinon), which improves nerve-to-muscle signal transmission, and immunosuppressants, such as prednisone and azathioprine (Imuran). But these vary in effectiveness, and some can have serious side effects.

IVIg involves giving the patient antibodies pooled from donors, via intravenous infusions. This may seem illogical, because the person with an autoimmune disease seems to have plenty of antibodies already. But results in other diseases (for example, the autoimmune disease Guillain-Barre syndrome) suggest the treatments may help. The infused antibodies seem to work by an unknown mechanism to stop the patient's autoimmune antibodies, perhaps by competing with them or blocking their activities.

To enter the trial, you must live near one of the following study sites because you'll have to visit the clinic every 10 days for 12 weeks. All five sites are MDA clinics.

MINNESOTA
University of Minnesota, Minneapolis
Adreinne Baranauskas, study coordinator
(612) 624-5978

NEW YORK
University of Rochester Medical Center, Rochester
Lynn Cos, study coordinator
(716) 275-7680

OHIO
Ohio State University School of Medicine, Columbus
Karen Downing, study coordinator
(614) 292-1234

TEXAS
University of Texas Southwestern Medical Center, Dallas
Lori Camperlingo, study coordinator
(214) 648-9038

University of Texas Health Science Center at San Antonio
Carla Sherman, study coordinator
(210) 567-1945

IVIG FOR INCLUSION-BODY MYOSITIS — WORTH THE COST?

A study of 19 people with inclusion-body myositis (IBM) found mixed results from treatment with intravenous immunoglobulins (see above). The study appears in the March 1997 issue of "Neurology."

In this study, there were only modest gains in strength in some muscle groups in those who got IVIg treatments, compared with those who got a placebo (inactive substance).

MDA grantee Richard Barohn suggests caution in an accompanying editorial, saying: "While we are awaiting further trials and newer potential drug therapies for IBM, the therapeutic dilemma of when to institute IVIg treatment and for how long will continue to challenge physicians who care for patients with IBM."

EMERY-DREIFUSS DYSTROPHY -- NEW RESEARCH, EASIER DIAGNOSIS

MDA grantee and Howard Hughes Medical Investigator Stephen Warren at Emory University in Atlanta has isolated the mouse form of the gene for Emery-Dreifuss muscular dystrophy (EDMD), a disorder that shows slowly progressive muscle wasting, early contractures (fixation of joints) and cardiac problems. The gene, which is on the X chromosome and carries instructions for the protein emerin, was identified as the cause of this form of muscular dystrophy in humans in 1994.

The isolation of the mouse form of the emerin gene will lead to the development of mice with the disease, a key research tool for understanding the disorder and testing treatments. The study is in the May 1997 issue of Mammalian Genome.

Skin cells or white blood cells can be used instead of muscle cells to diagnose EDMD, says an article in the January 1997 "Neuromuscular Disorders." The amount of the protein emerin, lacking in EDMD, can be measured in these cells, not just in muscle cells, because it's normally present in many tissues. Muscle measurements require a muscle biopsy, a fairly invasive procedure. Skin biopsies are much easier, and white blood cells can be obtained simply by drawing blood.

The skin cells give a slightly more accurate test result than the blood cells, the researchers say, but both types of tests may prove useful. Female carriers, who lack sufficient emerin, can also be detected using these new methods, according to the article.

Doctors may still want to do a muscle biopsy in some people with EDMD to see the condition of the muscle itself.

As genetic diseases come under scrutiny, researchers generally find there's a lot of variation in the nature and severity of these disorders, and EDMD is no exception. So far, 45 different EDMD-causing mutations in the same X-chromosome gene for the emerin protein have been found, causing varying disease courses. One mutation, found in a Japanese family and published in the March 1997 "Annals of Neurology," causes only mild skeletal muscle problems but serious cardiac abnormalities. The authors suggest that disease severity may be correlated with the particular genetic mutation, leading, for example, to a total lack of emerin, some emerin or severely damaged emerin. This situation would be similar to the differences between Duchenne and Becker muscular dystrophies, which depend on the amount of the protein dystrophin in muscle fibers.

MEMORY IMPAIRMENT IN MYOTONIC DYSTROPHY

People with mild muscle symptoms of myotonic muscular dystrophy (MMD) and small DNA expansions on chromosome 19 are likely to have normal intelligence but impaired memories, says a study in the March 1997 issue of the "Journal of Medical Genetics" that looked at 36 people with mild myotonic dystrophy.

Myotonic dystrophy is associated with an expanded piece of DNA on chromosome 19 and, in general, the larger the expansion, the more severe the disease. In severe cases, mental retardation and other thinking abnormalities are often found. This is the first study to seek out patients with only mild muscle weakness.

GENE FLAWS CAUSE SMA -- BUT HOW?

Researchers have known since early 1995 that there are two genes, lying close to each other on chromosome 5, that, when flawed, might lead to spinal muscular atrophy (SMA). The disorder involves loss of the motor neurons, muscle-controlling nerve cells in the spinal cord, and varying degrees of progressive weakness and wasting of muscles.

Since 1995, investigators have been trying to determine how one or both of these genes leads to the disorder. In the March 1997 issue of Human Molecular Genetics, a team headed by MDA grantee Kay Davies at the University of Oxford, England, describes a possible function for one of them. The SMN (for "survival of motor neuron") gene seems to code for a protein that affects how RNA is processed. RNA, or ribonucleic acid, is the chemical step that comes after DNA (deoxyribonucleic acid) in translating the genetic code into a protein. If the SMN protein affects RNA processing, it's possible that many proteins involved in motor neuron development or survival could be affected by mutations in the SMN gene.

Understanding how the SMN protein works and how its malfunction affects nerve cells is crucial to understanding and eventually treating SMA.

SNEAK PREVIEW OF GENE THERAPY WORKSHOP

As we go to press in May, the MDA Research Department and their counterparts in France at the Association Francaise Contre les Myopathies (AFM) are preparing for what promises to be an exciting joint conference May 30 and 31 in Tucson, Ariz.

Some 60 scientists and doctors from around the world will share their latest research and their thoughts about new directions in gene therapy and cell-based therapies, mostly in relation to Duchenne and Becker muscular dystrophies, but with application to other disorders.

Expected are lectures and discussions about new and not-so-new gene therapy vectors (delivery vehicles that carry genes into cells), including the adenovirus that's been used for several years, the newer adeno-associated virus, the herpes virus and the lentivirus. Non-viral vectors will also be discussed.

New information about how the immune system reacts to gene therapy and ways to coax the immune system into accepting new genes will be a major focus.

New twists on the old subject of myoblast transfer (transplantation of immature muscle cells) will be revealed, with a re-evaluation of the subject presented by long-time MDA adviser Louis Kunkel (whose team originally described the dystrophin gene and protein a decade ago).

The scientists will follow up on the exciting discoveries about utrophin, the protein that may be able to substitute for dystrophin, that occurred earlier this year in the laboratory of MDA grantee Kay Davies at the University of Oxford (England). Jon Tinsley of Davies' lab will update the researchers on what happens to mice with Duchenne dystrophy who've undergone utrophin replacement therapy. (Dystrophin is missing in Duchenne dystrophy and deficient in Becker dystrophy.)

MDA has invited to the meeting members of the Case Western Reserve University (Cleveland) team that recently created human artificial chromosomes. These chromosomes will allow scientists to study how a gene's immediate environment (such as other genes on the chromosome) affects its behavior -- whether it's turned on or off and how much protein it tells the cell to make. The new artificial chromosomes are expected to speed understanding of how genes, such as the one for utrophin, are regulated. They may also prove useful in delivering genes for gene therapy.

Watch for a report on this workshop in the near future.

CORRECTION ON ALBUTEROL TRIAL IN FSHD

The age range for the trial of albuterol in facioscapulohumeral muscular dystrophy is 18 to 60. There are two sites and they're both MDA clinics. The sites are:

NEW YORK
University of Rochester Medical Center, Rochester
Lynn Cos, study coordinator
(716) 275-7680

OHIO
Ohio State University Medical Center, Columbus
Karen Downing, study coordinator
(614) 292-1234