A major MDA research push to find ways to increase the body's production of the protein utrophin and alter its location in muscle fibers is under way, thanks to groundbreaking research published last fall by grantee Kay Davies at the University of Oxford in England.

Utrophin is a muscle protein that has many important similarities with the protein dystrophin, which is missing in Duchenne muscular dystrophy and insufficient in Becker dystrophy. Davies showed that mice born without dystrophin but with extra genes for utrophin didn't develop muscular dystrophy. In these dystrophin-deficient mice, utrophin was able to substitute for dystrophin, locking into place all around muscle fibers, where dystrophin would normally be found. The research suggests that increasing the body's production of utrophin and altering its location would probably compensate for a lack of dystrophin. Boys with Duchenne or Becker have normal utrophin genes, located on chromosome 6.

This February 1997, MDA grantees Kevin Campbell (University of Iowa), Jeffrey Chamberlain (University of Michigan), Davies, Stephen Hauschka (University of Washington), George Karpati (Montreal Neurological Institute), Joe Kornegay (University of Missouri), with Louis Kunkel (Children's Hospital, Boston), a member of MDA's Scientific Advisory Committee, and Donald Wood, MDA's director of science technology, were among an elite group of conferees at the Banbury Center of Cold Spring Harbor Laboratory in Cold Spring Harbor, N.Y.

The scientists planned a major research initiative to study the utrophin gene and find ways of increasing its production and distribution -- "upregulating" it. (An alternative approach, not yet ruled out, would be to use the utrophin gene instead of the dystrophin gene as gene therapy. The advantage of utrophin over dystrophin is that, since the boys already have normal utrophin, the immune system would likely be friendly to it.)

Two simultaneous approaches to utrophin upregulation will be undertaken. In one approach, the biotechnology company Oncogene Science (Uniondale, N.Y.) will screen existing compounds for their ability to increase utrophin production in mouse muscles that lack dystrophin. In the other approach, MDA-supported scientists and others will study how the utrophin gene normally works. The scientists suspect the utrophin gene is normally "turned off" in most of the muscle fiber; it's turned on only in one area of the fiber, the place where the nerve and muscle meet. It may be possible to turn on the utrophin gene so that utrophin is produced all over the fiber, thus allowing the protein to compensate for missing dystrophin.

Much of the utrophin research builds on years of MDA-supported study of genes in general and muscle genes in particular, said Wood, adding, "It's because of the incredible advances in this field in the last 10 years that we're moving so rapidly toward the real possibility of therapeutics."

A team led by MDA grantee Paula Clemens at the University of Pittsburgh has found that the immune system -- a major stumbling block to gene therapy of muscle -- may be reacting to a protein that would be easy to eliminate from gene therapy mixtures.

The protein, beta-galactosidase, marks" muscle cells that have received new genes by making them look blue under the microscope. The beta-galactosidase protein has been extremely useful in developing the tools of gene transfer, but until recently, it wasn't recognized that it would cause a response from the immune system, Clemens said.

Clemens cautions that beta-galactosidase may be only one of the triggers that alerts the immune system when gene therapy is attempted. Other possible culprits are proteins that are part of the viral shell used to deliver the dystrophin gene and the dystrophin itself.

The experiments were designed so that we could isolate the beta-gal variable," Clemens said. "Our current experiments are now aimed at isolating other variables, such as dystrophin and adenoviral proteins."

Repairing flawed genes, or blocking their activities, rather than putting in new genes, may be a future gene therapy reality, says MDA grantee Jeffrey Chamberlain at the University of Michigan. His comments are directed at two new approaches recently described in biotechnology journals.

In laboratory dishes, "antisense" therapy can block a gene's protein manufacturing capability, while natural chemicals known as ribozymes can cut and paste genetic material to change protein manufacturing instructions.

"At this point, all promising avenues are important to consider," Chamberlain says. "But until something actually works in a patient, it is too soon to make claims about the ultimate, or definitive, method." His laboratory and those of several other MDA grantees are concentrating on developing ways of delivering new dystrophin genes via hollowed-out viruses, but he hasn't ruled out other approaches.

Neuropsychologist Veronica Hinton at Columbia University's Gertrude Sergievsky Center in New York has an MDA grant to expand her study of strengths and weaknesses in the learning styles of boys with Duchenne and Becker. She's looking for volunteers with DMD or BMD and, where possible, their unaffected siblings, to take three hours of question-and-answer tests. Participants should be between 6 and 16 years old.

Some children with DMD and BMD are known to have learning problems, while others appear to do fine in school, Hinton says. Her preliminary findings have shown that some skills, such as the ability to understand verbal instructions, may be more affected than others.She's hoping to test children with a wide range of intellectual functioning.

If you'd like to participate in the study, call and leave your address and phone number with project coordinator Nancy Nereo at (212) 305-4324 or Hinton at (212) 305-2512.

FACIOSCAPULOHUMERAL MD

An MDA-supported trial of prednisone in eight people with facioscapulohumeral muscular dystrophy (FSHD) has now been analyzed and published in the January 1997 issue of Neurology. The researchers at the University of Rochester (N.Y.) and Ohio State University in Columbus found that prednisone given for 12 weeks didn't improve strength or increase muscle mass.

They say the negative result suggests the beneficial effects of prednisone in Duchenne may be disease-specific and not the result of a general positive effect of prednisone on dystrophic muscles.

Researchers at Ohio State University and the University of Rochester are expanding an MDA-supported trial of albuterol in FSHD. Albuterol belongs to a class of drugs known as beta-adrenergic agonists and isn't a steroid.

A small pilot trial suggested albuterol can increase muscle mass in FSHD. Now, the researchers will expand the trial to 90 patients. If you're interested in joining the trial, you must be between 18 and 80 years old, have facial muscle weakness, have weakness of either shoulder or foot muscles, be able to walk at least 30 feet with or without a cane or walker, and have difficulty raising your arms above your head. You won't be accepted into the trial if you've taken corticosteroids (such as prednisone) for longer than a year in the past, have used any corticosteroids within the past three months, are pregnant, have cardiovascular disease, are taking certain drugs that act on the nervous system, or have any medical or psychological condition that would make the interpretation of the study difficult.

If you think you're eligible, call Karen Downing, research coordinator at Ohio State, at (614) 292-1234. [please see correction to this announcement, issue 4-3]

MYOTONIC DYSTROPHY

If you have myotonic muscular dystrophy (MMD), you may be eligible to participate in a three-year study of heart problems, which are common in this disorder. There is room for 400 study participants.

Benefits to participants include regular electrocardiograms, genetic testing and careful monitoring of heart function. The investigators hope the long-term benefits will be better treatment of heart abnormalities associated with myotonic dystrophy.

The study will be based at the Krannert Institute of Cardiology at Indiana University School of Medicine, but several centers around the country have been asked to participate through their MDA clinics. Ask your MDA clinic director for details and whether your MDA clinic will be part of the project. You may also call Indianna University directly, research nurse Judy Hostetler, (317) 630-7126.

MYASTHENIA GRAVIS

Babies of mothers with myasthenia gravis (MG) are born with temporary symptoms of the disease about 20 percent of the time. The symptoms can be severe and can impair the baby's breathing, so doctors and parents want to be prepared for the problem.

The reason for the neonatal MG is that antibodies (proteins made by the immune system) that attack the mother's muscles in adult MG can cross into the fetal circulation and can sometimes affect the baby.

Now, European researchers writing in the January 1997 issue of Neurology say they have a reliable way to predict which babies will be born with MG symptoms, based on analyzing antibodies in the pregnant woman's blood.

The ratio of antibodies that can attack fetal muscles to antibodies that can only attack adult muscles can predict whether or not a baby will develop myasthenia symptoms, at least for the first pregnancy.

PREDNISONE UPDATE

Prednisone, a corticosteroid, has been shown to prolong walking by a few years in studies of boys with Duchenne. The drug's many side effects limit its use, but it's widely prescribed for Duchenne in the United States.

In December 1996, the European Neuro-muscular Centre, representing doctors from seven countries, released a statement that "steroids are potentially useful in DMD." They set up a European Consortium to "consider this matter in further detail, as well as other possible therapeutic agents which may arise in future." The statement also said, "At present the Consortium does not recommend the use of steroids in DMD outside carefully controlled studies."

Jon Andoni Urtizberea, a pediatric neurologist who heads the Department of Medical Affairs at the Association Francaise Contre les Myopathies (French MDA), said the Consortium's statement is a cautionary one. He says it's likely the group will propose guidelines for European steroid studies in the near future.

The risk of memory impairment from prednisone is considerable, say re-searchers at Wayne State University in Detroit in the December 1996 issue of Neurology.

In one study, they compared 25 people who had been taking at least 5 milligrams of prednisone a day for at least a year for conditions not related to brain function, with 25 people with similar diseases who weren't taking prednisone. They found the prednisone-treated group did significantly worse on tests of memory. In another study, they found similar memory impairment after only three months of prednisone treatment. The study agrees with several previous reports.

The type of memory problem suggests damage to the hippocampus, an area of the brain known to be involved in moving short-term impressions to long-term storage areas.

The researchers say the memory effects of prednisone should be considered before prednisone treatment is started, and that prednisone use should be looked at when doctors search for a cause of a person's memory loss.

People with myasthenia gravis and polymyositis were among the study participants.