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Offer Prednisone for DMD, Neurology Group Says

Side effects of prednisone can include weight gain and a Cushingoid face.

On Jan. 10, the American Academy of Neurology (AAN) released its long-awaited report on the use of corticosteroids (prednisone or deflazacort) in Duchenne muscular dystrophy (DMD). The report is also published in the Jan. 11 issue of Neurology.

It finds that corticosteroids are beneficial in DMD, but that some drawbacks to their use must be considered. To see the report for physicians and a version for families, go to “Practice Guidelines” on the AAN Web site at www.aan.com.

Known as a practice parameter, the report results from a review of relevant articles published from 1966 to 2004, of which 25 were chosen for detailed analysis. The AAN subcommittee preparing the report was composed mostly of MDA clinic directors and research grantees. Several of the 25 selected studies received MDA funding.

The report concluded that:

• Prednisone and deflazacort (the latter isn't available in the United States) are beneficial in the treatment of DMD. Seven high-quality studies showed a significant increase in strength, timed muscle function and pulmonary function with these medications.
• Effective initial treatments are 0.75 milligrams per kilogram of body weight per day for prednisone, or 0.9 milligrams per kilogram per day for deflazacort.
• The most frequent side effects are weight gain and the development of a Cushingoid facial appearance (rounded, puffy face).
• There are insufficient data comparing prednisone and deflazacort to determine whether deflazacort has fewer side effects.

The subcommittee’s recommendations included:

• Maintaining a daily dosage of 0.75 milligrams of prednisone per kilogram is best, but if side effects require a decrease in dosage, a gradual tapering to as low as 0.3 milligrams will still provide some improvement.
• Benefits and side effects of corticosteroid therapy need to be monitored. Timed function tests, pulmonary function tests, and age at loss of independent walking are useful to assess benefits. An offer of treatment with corticosteroids should include a discussion of risks.
• Possible side effects, such as weight gain, Cushingoid appearance, cataracts, short stature from slowed growth rate, acne, excessive hair growth, gastrointestinal symptoms and behavioral changes, need to be assessed. If a boy gains more than 20 percent over the estimated normal weight for his height in a year, the dosage of prednisone should be decreased to 0.5 milligrams per kilogram per day, with a further decrease to 0.3 milligrams after three to four months if excessive weight gain continues.
• Deflazacort at 0.9 milligrams per kilogram per day can also be used for the treatment of DMD in countries where it’s available. Patients taking deflazacort should be monitored for cataracts and weight gain.

Valerie Cwik, MDA’s medical director, said that while the guidelines are useful, they also identify many questions about corticosteroid therapy and DMD that remain unanswered.

Researchers Refining Naked DNA Delivery

MDA grantee Basil Petrof at the Meakins-Christie Laboratories and the Respiratory Division of McGill University in Montreal will continue to improve the efficiency of delivering “naked” (without viruses) DNA through the bloodstream to muscle cells, using funding from MDA that runs through 2007.

A group headed by Petrof that included MDA grantee George Karpati at McGill’s Montreal Neurological Institute recently found that reducing pressure from fluid buildup inside muscles may make delivery of naked DNA to muscles via arteries more effective.

The team, which published its findings online in Molecular Therapy on Oct. 28, found that by reducing the fluid pressure inside the leg muscles during the injection procedure, they could significantly increase the amount of DNA delivered to the muscles and minimize damage to muscle cells.

In experiments in pigs, the scientists reached some 60 percent of fibers in a muscle at the back of the leg after injecting DNA into a major artery in the thigh. Tests also indicated that lowering intramuscular fluid pressure buildup may have reduced damage to muscle fibers caused by such injections.

“Several groups are attempting to improve methods for delivering genes to muscle by injection into the bloodstream,” Petrof said. “We believe that intramuscular pressure monitoring is a simple and valuable tool for optimizing these efforts.”

Karpati added, “This method could be used for optimization of dystrophin gene delivery in appropriate clinical trials in Duchenne dystrophy patients.”

Better Tests Available for Duchenne, Beckers MDs

New tests will help families determine which mutation has led to Duchenne or Becker MD.

The Medical Genetics Laboratories at Baylor College of Medicine in Houston are now offering full screening for mutations (flaws) in the dystrophin gene, which underlie Duchenne muscular dystrophy (DMD) and Becker MD (BMD).

Standard tests only detect about 60 percent of DMD-causing mutations in the dystrophin gene and an uncertain percentage of BMD-causing mutations. However, it’s important for families to know exactly what mutation an affected member has, because such results may determine eligibility for a clinical trial, and may allow definitive prenatal and carrier testing.

The Baylor test, which was developed with MDA support of Madhuri Hegde in the Department of Molecular and Human Genetics, scans the dystrophin gene using denaturing high-pressure liquid chromatography (DHPLC), a process designed to detect almost all dystrophin mutations.

For more information, see the laboratory’s Web site at www.bcmgeneticlabs.org, or call (800) 411-GENE (4363).

Tests that examine the entire dystrophin gene are also offered at the Utah Genome Depot in Salt Lake City (www.genome.utah.edu/DMD/clinical_test.shtml; [801] 581-6956); and City of Hope National Medical Center’s Clinical Molecular Diagnostic Laboratory in Duarte, Calif. (www.cityofhope.org/cmdl/DMD.asp; [888] 826-4362).

SMA PROGRESS

Spinal muscular atrophy (SMA) is caused by a deficiency of the survival of motor neuron (SMN) protein, which is made by the SMN1 gene and to a far lesser extent by the SMN2 gene. Research is focused on improving SMN protein levels through insertion of SMN genes or increasing production from SMN2 genes.

Lentivirus Vector Delivers Genes to SMA Mice

Researchers at Ohio State University in Columbus and Oxford (England) BioMedica have developed a way of delivering therapeutic genes to mice with a disease resembling human SMA.

Mice that received SMN genes developed SMA symptoms later and lived a few days longer than did mice that received injections with no genes or no treatment at all.

The investigators first inserted the genes into transport vehicles (vectors) made from an altered version of the equine infectious anemia virus (EIAV), a member of the lentivirus family. They then injected the virus-coated genes into the muscles of the back legs, diaphragms, rib areas, faces and tongues of the SMN-deficient mice. They say the genes moved from muscle fibers up nerve fibers.

The authors, who published their results in the December issue of the Journal of Clinical Investigation, write that the findings “are indicative that gene transfer using lentivector expressing SMN at onset of disease induces not only an extension in life span, but also results in a delay in the motor phenotype [movement functions] in a severe model of SMA.”

They also note, however, that the effects on the mouse disease were surprisingly minimal, given that SMN was found in a large percentage of examined nerve cells.

The study authors included Arthur Burghes, a molecular biologist at Ohio State who, with MDA funding, contributed significantly to the understanding of SMA genetics in the late 1990s.

Drug Screen Under Way

A project funded by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health is searching for chemical compounds that can be developed into medications to treat SMA.

Known as the SMA Project (see www.smaproject.org), the drug screen is aimed at finding substances that increase SMN2’s output of the SMN protein.

“We have good candidate drugs from studies in other systems,” grantee Michael Terns, associate professor of biochemistry and molecular biology at the University of Georgia in Athens, said. “In addition, there are libraries of compounds available for testing to see if protein concentrations go up without having to know the mechanism behind it.”

The Georgia researchers will use NIH-approved human embryonic stem cells to test the ability of compounds to increase SMN production. Additional grants were given to Johns Hopkins University in Baltimore and Ohio State University in Columbus.

Indoprofen Increases SMN

A team of investigators has found that indoprofen, a nonsteroidal anti-inflammatory agent, slightly increases production of the needed SMN protein in cells taken from people with severe SMA.

Drug responses from cells in a lab dish don’t always match responses in animals or people, but cell-based screens are often a first step toward drug discovery

The researchers, in the November issue of Chemistry & Biology, say the drug also led to more gems, structures that are reduced in SMA-affected cells. And SMA-affected developing embryos showed a trend toward greater survival when their mothers were given indoprofen.

Among the study team members were Glenn Morris of the Robert Jones and Agnes Hunt Orthopaedic Hospital in Oswestry, United Kingdom; Arthur Burghes of Ohio State University in Columbus; and Elliot Androphy of the University of Massachusetts in Worcester, all of whom have received MDA funding to study SMN.

The authors note that no other tested compounds from this class of anti-inflammatory medications increased SMN production.

The indoprofen finding wasn’t a result of the NINDS SMA Project (above).

CLINICAL TRIALS AND STUDIES

DMD Gene Therapy Trial Passes First Safety Test

The Recombinant DNA Advisory Committee (RAC), part of the National Institutes of Health (NIH) in Bethesda, Md., voted on Dec. 16 that an MDA-supported gene therapy safety trial — the first such trial in boys with Duchenne muscular dystrophy (DMD) in the United States — can move forward. Next steps include further animal safety testing and approval by the U.S. Food and Drug Administration (FDA).

	R. Jude Samulski

The study, once approved, will be conducted by neurologist Jerry Mendell of Columbus Children’s Research Institute, part of Ohio State University; R. Jude Samulski, a virus specialist at the University of North Carolina in Chapel Hill; and Xiao Xiao, a molecular biologist at the University of Pittsburgh. Samulski and Xiao are part of Asklepios Biopharmaceutical, a biotechnology company in Chapel Hill.

	Xiao Xiao

The investigators plan to test the safety of a laboratory-engineered gene for the muscle protein dystrophin, tucked inside a modified adeno-associated virus (AAV). (See “Bridge Over Troubled Waters,” January-February.)

	Jerry Mendell

If all goes according to plan, six boys with DMD who are at least 10 years old will receive injections of the AAV-encapsulated genes into one biceps muscle, while the opposite biceps receives placebo (sham) injections.

After about six weeks, samples of the muscles will be examined for evidence of dystrophin production and signs of damaging reactions, such as an unwanted immune response. The participants will undergo many other types of safety testing during and after the injections.

The trial isn’t seeking participants at this time.

Sudden Cardiac Death a Risk in Type 2 MMD

In a study of type 2 myotonic dystrophy (MMD2), sudden death from cardiac causes occurred in four people, three of whom had no prior symptoms, report researchers at the University of Minnesota in Minneapolis and several centers in Germany.

The investigational team included MDA research grantees Laura Ranum and John Day at the University of Minnesota-Twin Cities. Day also directs the MDA clinic at Fairview-University Medical Center in Minneapolis.

The researchers studied medical records and other data from 297 people with genetically confirmed MMD2.

The four who died had the “dilated” type of cardiomyopathy, and two of them also had scarring of heart cells that conduct signals through the tissue.

In their report in the Dec. 28 issue of Neurology, the authors write, “Our observations reveal that DM2 [type 2 MMD] patients are at risk for severe cardiac complications that need close cardiac surveillance.”

While the cardiac problems associated with type 1 MMD have been the subject of much study in recent years (see "Heart Problems," below), the extent to which MMD2 is associated with these problems has only recently become clear.

“These findings substantiate the need for patients with both types of MMD to have frequent clinical evaluations to assess heart function,” Day said.

Last year, researchers at the University of Wurzburg in Germany found that people with MMD2 can have subtle heart problems long before they develop symptoms and that older MMD2 patients can develop cardiomyopathy, a degeneration of cardiac muscle cells (see “Research Updates,” January-February).

Heart Problems in MMD1 Often Require Pacemaker

A ongoing study of heart problems in type 1 myotonic dystrophy (MMD1) that began in 1997 has released two sets of interim results.

The study is being conducted under the direction of cardiologist William Groh at the Krannert Institute of Cardiology of Indiana University in Indianapolis and has had support from medical electronics manufacturer Medtronic and from MDA.

As of June, 440 patients were enrolled in the study. In a subsection, six people had a device implanted underneath the skin of the chest to constantly record heart rate and rhythm. Serious problems were detected in three people, and two received an electronic device to correct problems.

As of January, 57 participants (13 percent of the 440) were noted to have entered the study with a diagnosed heart problem. At study entry, nine of them (2 percent) had a pacemaker. By January, 37 (9 percent) had had a pacemaker inserted.

Residents of the Indianapolis area who believe they have MMD1 are still being enrolled. Contact clinical research coordinator Miriam Lowe at (317) 962-0080, (800) 843-2786 or milowe@iupui.edu.

Etanercept for MG Shows Promise, Risks

Doctors at the University of Illinois and Rush University Medical Center in Chicago and the University of Texas at Galveston have found that the drug etanercept (Enbrel) may offer hope to some people with myasthenia gravis (MG) who need relatively high doses of corticosteroids, such as prednisone.

In the autoimmune disease MG, the immune system mistakenly attacks the part of the muscle cell that receives signals from a nerve cell, leading to fluctuating weakness.

Etanercept, which has FDA approval for the treatment of arthritis and psoriasis, blocks the action of tumor necrosis factor (TNF), a substance secreted by cells of the immune system that has been implicated as a contributor to MG.

The doctors originally enrolled 11 people with MG, all of whom had needed at least 25 milligrams of prednisone every other day for more than six months to control symptoms. This is a potentially toxic corticosteroid level.

Six of the 11 patients improved with etanercept, administered by injection twice a week, based on measures of muscle strength and the ability to successfully taper their prednisone doses. Two others withdrew when their disease worsened.

The study team, which included MDA grantees Erdem Tuzun and Premkumar Christadoss at the University of Texas at Galveston, published its findings in the Dec. 28 issue of Neurology. (Amgen, which markets Enbrel, contributed to funding for the trial.)