CREATINE MAY HELP IN MD, ALS

Creatine, an over-the-counter supplement popularized by athletes for its ability to produce "bursts" of energy, may also have benefits for people with some neuromuscular disorders.

MDA-funded researcher M. Flint Beal of Cornell University Medical Center in New York and colleagues showed that creatine was twice as effective as the prescription drug riluzole in extending the lives of mice with a genetic type of amyotrophic lateral sclerosis (ALS). Beal's work appears in the March issue of the journal Nature Neuroscience.

Meanwhile, a Canadian study by Mark Tarnopolsky and Joan Martin of McMaster University in Ontario found that creatine increased muscle strength in people with several types of muscular dystrophy and other myopathies. The researchers' work was published in the March issue of Neurology.

MDA is planning a multicenter clinical trial to determine the effectiveness of creatine supplementation in humans with ALS, and is reviewing applications for trials of creatine in other neuromuscular disorders. More information about the trials, along with answers to frequently asked questions about creatine, can be found at MDA's Web site (www.mda.org) or by calling (800) 572-1717.

Creatine isn't a prescription drug, but doctors advise that anyone with a neuromuscular disease should consult with an MDA clinic director before taking it.

SKELETAL MUSCLE LOSS MAY HARM HEART IN DMD, BMD

Cardiac muscle damage is common in Duchenne and Becker muscular dystrophies (DMD and BMD), disorders caused by a complete (in DMD) or partial (in BMD) loss of the muscle protein dystrophin. (See "The Heart Is a Muscle, Too.")

Dystrophin normally plays an important role in both skeletal and cardiac muscle cells, so specialists have long assumed that the cardiac damage in these disorders is primarily due to a lack of the protein in the heart.

Now, MDA grantees at McMaster University in Hamilton, Ontario, Canada, have lent support to the theory that other factors are important. Mice missing only dystrophin normally don't show much muscle degeneration in either the heart or the skeletal muscles, with the exception of the diaphragm. But, when researchers Michael Rudnicki and Lynn Megeney developed mice missing not only dystrophin but also another key skeletal muscle protein, they found their hearts were severely affected.

Rudnicki and Megeney bred dystrophin-deficient mice that also lacked a protein known as MyoD, which is needed for skeletal muscles to regenerate after injury but isn't needed by the heart. They saw severe heart damage in the animals, however, and speculate that it's the ongoing damage to skeletal muscle that led to it.

The problem could result from increased mechanical stress on the heart because of changes in blood flow and exercise, or it could be due to altered chemical signals from degenerating skeletal muscle cells, the researchers say.

The study supports the use of treatments to reduce the strain on the heart, Rudnicki says. Such treatments are already commonly prescribed in DMD and BMD. Megeney, who recently moved to the Centre for Molecular Medicine at Ottawa General Hospital, is targeting two specific proteins that may be involved in the heart damage as possible avenues for future therapies. He's received a new MDA grant for this work.

The MyoD study is in the Jan. 5 issue of Proceedings of the National Academy of Sciences USA.

MYOTONIC DYSTROPHY STUDY STILL OPEN

Neurologist and MDA research grantee Richard Moxley at the University of Rochester (N.Y.) Medical Center is investigating the causes of the muscle wasting, weakness and metabolic abnormalities seen in myotonic muscular dystrophy (MMD). The study, sponsored by the National Institutes of Health, has been open since 1997 and is comparing findings in people with myotonic dystrophy to those in people with other neuromuscular diseases. The researchers hope to identify specific alterations in body function that could eventually lead to new therapies.

They're looking for participants with myotonic muscular dystrophy, proximal myotonic myopathy (PROMM), facioscapulohumeral muscular dystrophy (FSHD) and Charcot-Marie-Tooth (CMT) disease, type 1A only. Participants must be between 21 and 60 years old, must not be obese and must be able to walk.

The study requires two inpatient stays at the University of Rochester General Clinical Research Center. The first visit is five days and the second visit is three days. For information, call nurse Cheryl Barbieri at (716) 275-5409 or e-mail research@mail.neurology.rochester.edu.

THERAPIES PURSUED FOR ACID MALTASE DEFICIENCY

Acid maltase deficiency (AMD), also known as Pompe's disease, is a genetically inherited metabolic disease that causes severe muscle weakness due to a lack of the enzyme required to break down glycogen.

MDA researchers have been pursuing two types of therapies to treat AMD. One involves replacing the missing acid maltase enzyme by injecting it into patients (enzyme replacement therapy), and the other involves introducing the genetic instructions for making the acid maltase enzyme into patients' cells (gene therapy).

"Development of enzyme replacement therapy has progressed extensively over the last three years," says Alfred Slonim of the Pediatrics Department of North Shore Hospital in New York.

Two groups are working to produce an injectable form of the acid maltase enzyme. The first is a Dutch company, Pharming Pharmaceuticals, which is using genetically engineered rabbits to produce the enzyme in their milk. Pharming recently started a small clinical trial in Europe and plans a larger clinical study in Europe and the United States.

MDA grantee Y.T. Chen of Duke University in Durham, N.C., in collaboration with Synpac Pharmaceuticals, is also working to develop an enzyme replacement therapy. Chen is making and purifying the enzyme in a laboratory cell line derived from Chinese hamster ovaries. The form of the enzyme produced by Chen was recently granted orphan drug status by the Food and Drug Administration and phase 1 clinical trials are planned.

Gene therapy for AMD is being pursued by several MDA researchers, including Paul Kessler of Johns Hopkins University in Baltimore, who is working with Barry Byrne of the University of Florida in Gainesville and Andreas Amalfitano of Duke University. Kessler and Byrne have been testing an adeno-associated virus (AAV) vector as a carrier for the acid maltase gene, and have successfully corrected the deficiency in a mouse model of the disease.

Kessler and Byrne are cautiously optimistic about the approach and predict that they'll begin recruitment for human gene therapy trials in January 2000. The first trial is expected to look at effectiveness as well as safety. They suggest that a blend of enzyme replacement therapy and gene therapy may yield the best results.

RESEARCHER DEVELOPS GENE 'CONTROL SWITCH'

Gene therapy -- the insertion of new genes -- offers exciting possibilities for treatment of both genetic and non-genetic diseases. But among the challenges remaining is a method for regulating how much protein is produced from a gene at any given time.

Normally, our cells "decide" how much of a protein to make from the gene, or "recipe" for that protein. However, when we introduce a gene into a cell artificially, through gene therapy, the gene isn't hooked up to the cell's normal control system. Doctors would like to have a way to regulate the amount of protein made from artificially inserted genes.

MDA grantee James Wilson, who heads the Institute for Human Gene Therapy at the University of Pennsylvania in Philadelphia, was on a team that's developed a method for a drug-responsive control system that they say will work in at least some forms of gene therapy. In the system that the researchers developed and tested in animals, the gene for a blood-cell-forming protein (erythropoietin) was injected with two other genes that "turn on" erythropoietin production in the presence of the drug rapamycin. When the animal takes rapamycin by mouth, the gene is turned on by the molecular switch. Without rapamycin, the gene shuts off, and no erythropoietin is made.

Wilson's team developed the rapamycin gene switch in conjunction with scientists at Ariad Pharmaceuticals of Cambridge, Mass. The rapamycin study is in the Jan. 1 issue of Science.

TEAM DISCOVERS NUCLEAR GENE AFFECTING MITOCHONDRIAL DNA

Michio Hirano of Columbia University in New York, working with long-time MDA grantee Salvatore DiMauro, also of Columbia, recently discovered the first mutation in a nuclear gene that interferes with communication between the nucleus of the cell and the DNA of the mitochondria (the cell's "power plants"). The work was published in the Jan. 29 issue of Science.

The researchers found that mutations in the nuclear gene for an enzyme called thymidine phosphorylase are responsible for a mitochondrial disorder known as MNGIE, or mitochondrial neurogastrointestinal encephalopathy. As the name implies, this disease affects a number of systems, including the voluntary muscles, nervous system and digestive system. The involvement of the digestive system can be particularly devastating in this disorder and often leads to malnourishment at a young age.

Researchers already knew that large deletions in the mitochondrial DNA of people with MNGIE are probably the immediate cause of the problems associated with this disorder, but it wasn't clear how these deletions occurred. A communication problem between the nucleus and the mitochondria was suspected, however, because the disease had been genetically linked to a location in the nuclear DNA.

Now Hirano has demonstrated that the nuclear gene that encodes thymidine phosphorylase is mutated in 12 out of 12 unrelated people with MNGIE, even though these people have different deletions in their mitochondrial DNA.

The researchers suspect that a lack of thymidine phosphorylase activity resulting from these mutations may cause deletions in the mitochondrial DNA by limiting the availability of some nucleotides (DNA "building blocks") in the mitochondria.

Now that researchers know how mitochondrial DNA deletions occur in MNGIE, therapies can be designed to compensate for the decreased activity of thymidine phosphorylase. Hirano suggests that this might be accomplished either by injecting the missing enzyme, or increasing directly the levels of nucleotides that are in short supply.

FSHD STUDY SEEKS PARTICIPANTS

MDA grantees Rabi Tawil and Denise Figlewicz at the University of Rochester (N.Y.) are looking for people with facioscapulohumeral muscular dystrophy (FSHD) to participate in a research study to determine the molecular cause of this disorder. The study involves one visit to Rochester to obtain blood and muscle samples (biopsies). Of particular interest are identical twins, only one of whom is affected by FSHD.

Contact study coordinator Lynn Cos at (716) 275-7680, or e-mail lcos@mail.neurology.rochester.edu.