An experimental drug being developed to treat obesity and high blood lipid (fat) levels also may have promise for the treatment of Duchenne (DMD) and Becker (BMD) muscular dystrophies, according to new, MDA-supported research from the University of Ottawa.
MDA grantee Bernard Jasmin and graduate student Pedro Miura coordinated and led the study team, which published results online Sept. 10, 2009, in Human Molecular Genetics.
Mice with a disease similar to DMD showed significant muscle fiber improvement after being treated with a compound called GW501516, which is being developed to treat obesity by the pharmaceutical company GlaxoSmithKline.
The compound increased levels of the muscle protein utrophin in the DMD mice. Utrophin has been found to partially compensate for dystrophin, the muscle protein that’s deficient or missing in BMD and DMD.
Until now, relatively few experiments to increase utrophin have utilized substances that are likely to be developed into drugs in the near future.
|Clusters of proteins are embedded around the periphery of each muscle fiber and help keep the fiber intact during muscle contractions. A lack of the protein dystrophin leads to DMD, while loss of any of the four sarcoglycan proteins leads to limb-girdle muscular dystrophy. These protein clusters are mainly linked to the inside of the muscle fiber by dystrophin, although utrophin performs this function on some parts of the fiber border. The new experiments in dystrophin-deficient mice support the hypothesis that utrophin can at least partially compensate for the loss of dystrophin and show that utrophin levels can be increased in mice by GW501516.|
About DMD and BMD
DMD, a genetic disease that involves progressive degeneration of voluntary and cardiac muscles, results from any of a number of mutations in the gene for dystrophin, a protein that plays a key role in protecting muscle fibers from destruction when they contract.
Dystrophin normally is located near the membrane that surrounds each fiber. Without it, these membranes are much more fragile. Almost no dystrophin is produced in the muscles of DMD patients.
In a related condition, Becker muscular dystrophy (BMD), some functional dystrophin is produced, although not enough to allow normal maintenance of muscle tissue. BMD is generally less severe and usually allows for longer survival than DMD, but cardiac abnormalities can be serious and often shorten life span.
Among the many avenues being pursued in DMD and BMD research is raising levels of utrophin, a muscle protein that's very similar to dystrophin. Utrophin is normally present in muscle fibers during fetal development and remains in the mature fibers at the places where nerve and muscle fibers meet. Sufficient levels of utrophin seem capable of at least partially compensating for dystrophin’s absence in muscle fibers.
DMD and BMD patients have normal utrophin genes and produce plenty of utrophin protein, but utrophin protein from these genes isn't sufficient to compensate fully for the missing dystrophin. (It may compensate somewhat for the loss of dystrophin in patients.)
Raising utrophin to sufficient levels by injecting utrophin genes or protein or by increasing utrophin production from existing genes has been a goal of ongoing laboratory investigations for more than a decade. (See Utrophin Strategies Excite Duchenne Researchers, Utrophin Gene Therapy Benefits DMD Mice and Utrophin Gets In.)
About the new findings
Mice with a DMD-like disease started receiving GW501516 at 5 to 7 weeks of age, a time when muscle degeneration is already under way in these rodents. After four weeks, the treated mice had 1.5 times more utrophin in their muscle fibers than untreated DMD mice.
When compared to their untreated counterparts, the treated mice also had tougher muscle-fiber membranes and fibers that were better able to resist damage from contractions. Muscle fibers from the treated mice showed less drop in force after contraction than did fibers from untreated mice.
"These data strongly suggest that GW501516 treatment might have important therapeutic benefits for DMD patients even after initial symptoms of muscle wasting arise," the researchers write.
Meaning for patients
Several strategies to increase the utrophin content of muscle fibers have shown promise, lending "proof of principle" to this approach. Until now, however, relatively few have utilized substances that are likely to become treatments in the near future.
In contrast, GW501516 is in development by a major pharmaceutical company for common conditions, such as obesity and elevated blood lipids.
If the results of current clinical trials show GW501516 is safe and effective in treating these conditions, it will likely be widely marketed and could become available for experimental use in DMD.
In addition, Jasmin says, many smaller biotech companies have developed similar compounds over recent years and are awaiting results in laboratory studies or clinical trials. Thus, there may be many variants of the drug, some with increased efficacy, that could become available in the future.
However, he notes, additional testing in other animal models of DMD may be needed before such types of drugs will be tried in DMD or BMD patients.