Aug. 24, 1997 ST. LOUIS -- For the first time, scientists have developed a mouse with realistic symptoms of Duchenne muscular dystrophy, a devastating muscle disease that usually kills patients by age 20.
This work should greatly advance the search for better treatments, the researchers say. "The only effective way to develop new therapies is to test them in an experimental animal with symptoms of the disease," says Joshua R. Sanes, Ph.D., who led the team. Sanes is a professor of anatomy and neurobiology at Washington University School of Medicine in St. Louis.
The mouse, described in the Aug. 22 issue of Cell, develops muscle wasting and heart disease and dies by early adulthood. "This is the first animal suitable for studying the effects of Duchenne on both skeletal muscle and the heart," says R. Mark Grady, M.D., an instructor in pediatric cardiology and lead author of the paper. "That's important because these children would die of heart failure as young adults even if their muscles were cured. So it would be a mistake to look for a treatment for just the muscle symptoms." Duchenne muscular dystrophy is the most common disorder of muscle, affecting mostly boys. Between 20 and 30 out of every 100,000 boys born in the United States this year will develop Duchenne, and 3 out of every 100,000 have it right now. There currently is no effective therapy, though steroids sometimes are used to slow the relentless progression of the disease.
Symptoms usually begin between the second and fifth birthday, when a child starts to fall and have difficulty getting up. By late childhood or early adolescence, the muscles become so weak that crutches give way to a wheelchair. Because the muscles needed for breathing also are destroyed, patients eventually need a ventilator and often die from respiratory disease.
The disorder results from a defect in the gene for an enormous protein called dystrophin, which forms part of the scaffold in muscle fibers. Scientists who want to study the consequences of dystrophin deficiency in an experimental animal have had to rely on a mouse called mdx, which has a natural mutation in the gene. But mdx mice have fairly normal muscles and no apparent heart problems, and they don't get progressively sicker or die young. One possible explanation involves another muscle protein called utrophin, which is very like dystrophin. Mice might contain enough of this protein to stabilize muscle when dystrophin isn't there to do the job. But the larger muscle fibers of humans would deteriorate in the absence of dystrophin, even when utrophin levels were normal.
Grady began testing this idea in 1996 by removing the utrophin gene from a mouse, creating a creature that also had few symptoms. But when the team bred this utrophin-deficient mouse with the mdx mouse, they obtained the mouse described in Cell. Lacking both utrophin and dystrophin, this animal ends up in the same predicament as children with Duchenne. Its symptoms include decreased activity, a waddling gait, stiff limbs, curvature of the spine and death by early adulthood.
The researchers used a variety of tests to determine the underlying causes. By viewing stained muscle samples under the microscope as the mice matured, they found that the muscle degenerated and partly regenerated and degenerated again, replacing itself with connective tissue. So the mouse had the same type of muscle-wasting as children with Duchenne.
Electrophysiological tests showed that the muscles of the double mutant were not nearly as strong as those of normal mice or mice that lacked only utrophin or dystrophin. In fact, they generated only about half as much force when their nerves were stimulated. Further tests showed that this weakness resembled that seen in the muscular dystrophies, which involve muscle defects, rather than in the neuropathies, where muscle-controlling nerves are damaged, or the myasthenias, where connections between nerve and muscle are defective.
The researchers also observed damaged muscle cells in the hearts of double mutants that were not present in the hearts of the other mice. By injecting dye that stains leaky cells, they determined that some of the heart cells were dying. So the double mutant develops severe heart disease, like patients with Duchenne.
The mouse now can be used to learn more about the mechanisms of Duchenne. "It also will greatly facilitate research directed at finding an effective therapy for the disorder in humans," says Ronald J. Schenkenberger, director of research and patient services administration at the Muscular Dystrophy Association.
The work also suggests a new strategy for treatment. "Other researchers recently showed that you can make mdx into a symptom-free mouse by making it synthesize huge amounts of utrophin," Sanes says. "But the double mutant shows that just removing the normal, small amount of utrophin makes mdx very sick. So turning up the human utrophin gene by just a modest amount might make Duchenne patients rather healthy."
Learning how to turn up a gene that already is functioning should be easier than developing gene therapy techniques to replace the faulty dystrophin gene, the researchers say. "If you could take a boy with Duchenne and make him as healthy as an mdx mouse, that would be a great triumph," Sanes says.
Grants from the Muscular Dystrophy Association and the National Institute of Neurological Disorders and Stroke supported the research.
Grady RM, Teng H, Nichol MC, Cunningham JC, Wilkinson RS, Sanes JR. Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: A model for Duchenne muscular dystrophy. Cell 90, 729-738, Aug. 22, 1997.
Note: Another paper describing the production of a mouse lacking both dystrophin and utrophin appears in the same issue of Cell. That research team is headed by Kay Davies, Ph.D., University of Oxford, England.
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