GENE THERAPY TRIALS AWAIT OFFICIAL OKs

Plans for MDA-sponsored clinical trials to test the safety of gene therapy in Duchenne, Becker and limb-girdle muscular dystrophies are going through the necessary steps for approval from the Food and Drug Administration, and at least the first stages of these trials could begin before the end of the year (see story).

A spokesman for the Association Française Contre les Myopathies (French MDA) confirmed reports that two biotechnology companies, Transgene and Schering-Plough, will sponsor a European clinical trial of tolerance of gene therapy in adults with Duchenne dystrophy by the end of the year. This trial is awaiting approval from European regulatory agencies.

To keep up with current developments, check MDA's Web site at www.mda.org.

RESEARCHERS PROBE MYASTHENIAS

The word "myasthenia" literally means muscle weakness, but these days it's used only to describe a few specific conditions that involve defects in the way signals travel from nerve to muscle. Research is advancing in two kinds of myasthenia: the autoimmune ("self"-immune) disorder myasthenia gravis (MG), in which the body's immune system mistakenly attacks and destroys the part of the muscle that receives signals from the nerve -- the acetylcholine receptor -- and slow-channel congenital myasthenic syndrome, a form of myasthenia caused by genetic abnormalities that change the way the acetylcholine receptor functions.

Using the immune system to flush out its own misbehaving cells in MG is a strategy being studied by MDA grantee Daniel Drachman of Johns Hopkins University School of Medicine in Baltimore. Drachman's team gave rats acetylcholine receptors from another species, causing their immune systems' T cells -- key players in the immune response -- to gear up for an attack on all acetylcholine receptors, including their own.

"It's as if we put a chalk mark on the activated T cells," Drachman says, noting that that's the best way to recruit the "pivotal cells" involved in the autoimmune reaction.

The researchers then used two strategies to eliminate the activated T cells without disturbing other T cells or other parts of the immune system. First, they blocked a key signal needed by T cells to launch an attack; without this signal, these cells lapse into a state of long-lasting, possibly permanent, inactivity, Drachman says. They also used a compound based on diphtheria toxin that was genetically engineered to kill only activated T cells.

Both strategies were effective, especially when used together. Drachman says he's now trying a safer method in the rats that he hopes can eventually be used in humans.

Instead of giving the rats acetylcholine receptors from another species, which actually gives them MG while recruiting their activated T cells, he's giving them a modified version of their own receptors. A modified rat receptor, he hopes, will still recruit activated T cells that will then be vulnerable to the T-cell elimination strategies, but, he says, it probably won't cause disease.

The study is reported in the July 1 issue of the Journal of Neuroimmunology.

Azathioprine plus corticosteroids may be better than steroids alone in MG, say British researchers at the University of Oxford and the Walton Centre for Neurology and Neurosurgery in Liverpool.

Among the many treatments for MG are corticosteroids that dampen the immune response, particularly prednisone and prednisolone, and other types of immunosuppressive drugs, such as azathioprine. Doctors have long used these drugs in combination to maximize benefits and minimize side effects, but few controlled studies have been done.

A new study published in the June issue of Neurology confirms what physicians have long suspected: Adding azathioprine (often known by the brand name Imuran in the United States) to prednisolone (very similar to prednisone) reduced the necessary dose of prednisolone, led to fewer treatment failures and fewer drug side effects, and resulted in longer remissions. Eighteen patients were studied for three years.

The drug quinidine may be useful in one form of genetic myasthenia, according to MDA grantee Andrew Engel of the Mayo Clinic and Foundation in Rochester, Minn. Engel co-authored a study of the treatment, which is published in the April issue of Annals of Neurology.

The disorder studied is slow-channel congenital myasthenic syndrome (SCCMS), in which abnormalities in the acetylcholine receptor cause a channel in the middle of the receptor to stay open too long. After experiments suggested that the drug quinidine -- normally used to treat abnormal heart rhythms -- could shorten the "open time" of the channel, the researchers decided to try it in people with SCCMS.

Six patients took the drug. One became allergic to it after a week; the others tolerated it well and showed significant improvement in strength after 30 days. One had respiratory difficulties after three months on quinidine, which were successfully managed.

The authors note that quinidine is specifically for SCCMS and could be harmful in other forms of myasthenia.

CONDUCTION DEFECTS COMMON IN MYOTONIC MD

William Groh of the Krannert Institute of Cardiology at Indiana University School of Medicine in Indianapolis has released a report on the first year of a multicenter study of heart problems in myotonic muscular dystrophy (MMD), which began last year at about 25 MDA clinics. The study confirms that heart problems of the type known as conduction defects are common in this form of MD.

These affect the way signals that resemble electrical transmissions travel through the heart and regulate the heartbeat. Seventy percent of those studied had abnormal electrocardiograms, but only 13 percent had cardiac symptoms, such as fainting episodes.

The study also shows that, at least in middle-aged people, the severity of the heart problem is closely correlated with the size of the genetic defect that underlies myotonic dystrophy. The investigators studied 220 people with myotonic dystrophy.

An interesting finding was that, in the younger age group (18-34), and in the older group (over 55), the correlation between the genetic defect and the heart defect was not as strong as in the middle-age group (35-55).

The researchers speculate that it may take time for the genetic defect, which is an expanded stretch of DNA on chromosome 19, to affect the heart. This would mean that even a small DNA defect could eventually take its toll on the heart of an older person, while even a large one might not affect a young person.

The research aims to improve diagnosis, prevention and treatment of the heart complications common in myotonic dystrophy. Funding is from Medtronic Corporation of Minneapolis, makers of pacemakers and other implantable medical equipment.

The study is still open. If you'd like to be involved, have your neurologist call Groh at (317) 630-6629 or send e-mail to wgroh@iupui.edu.

All testing can be done at your participating MDA clinic. No travel to Indianapolis is required.

NEW GENES IDENTIFIED IN THREE DYSTROPHIES

Three new genes have recently been implicated in muscular dystrophies. The findings will lead to better diagnosis of these disorders and may lead to treatments.

A chromosome 2 gene that's involved in two muscular dystrophies and codes for a newly named protein, "dysferlin," was identified by an international team headed by MDA grantee Robert Brown of the Day Neuromuscular Research Laboratory of Massachusetts General Hospital in Charlestown. Mutations in this gene can cause limb-girdle muscular dystrophy, a disorder in which weakness begins in the shoulder and pelvic area muscles. At least six other genes can, when flawed, also cause LGMD.

Mutations in the dysferlin gene can also cause a different dystrophy known as Miyoshi myopathy (covered by MDA as a distal muscular dystrophy), which begins in a calf muscle and for which no genes have previously been identified. The function of dysferlin isn't yet clear, but the investigators say it may have to do with the formation of membranes that surround structures inside cells. The findings are published in the September issue of Nature Genetics.

A chromosome 3 gene for a protein known as caveolin-3 has been named as another cause of LGMD by a group of researchers from Italy and the United States, who published their findings in the April issue of Nature Genetics. Caveolin-3 appears to be associated with the muscle fiber membrane, as are many other proteins that, when missing or deficient, lead to various forms of muscular dystrophy.

A gene on chromosome 9, which codes for the newly named protein "fukutin," has been named as a culprit in Fukuyama-type congenital muscular dystrophy, a form of the disease that's usually found in people of Japanese descent. It involves early-onset muscle weakness and brain malformations.

Japanese scientists found the gene and described its protein product, publishing their findings in the July 23 issue of Nature. They say fukutin probably isn't part of the muscle membrane but that it may interact with membrane proteins. Another form of congenital MD has been previously identified as being caused by a deficiency of the protein laminin, which attaches to muscle membrane proteins.