Research Updates September-October 2008

Article Highlights:

The latest information on research news as of August 2008

by Quest Staff on September 1, 2008 - 12:28pm

QUEST Vol. 15, No. 5

This article contains items about: Duchenne muscular dystrophy, Becker muscular dystrophy, limb-girdle muscular dystrophy, Charcot-Marie-Tooth disease

Viagra improved heart function in DMD mice

A recent study has found treatment with sildenafil (Viagra) significantly improved heart function in mice missing the protein dystrophin and showing a disease resembling Duchenne muscular dystrophy (DMD). Heart-muscle deterioration (cardiomyopathy) is a leading cause of death in boys and men with DMD and the closely related Becker muscular dystrophy (BMD).

A research team coordinated by Christine Des Rosiers at the University of Montreal, which included MDA grantee Basil Petrof at McGill University in Montreal, announced its findings May 13 in Proceedings of the National Academy of Sciences.

The idea of treating dystrophindeficient mice with sildenafil was based on previous studies suggesting that the hearts of these mice are more susceptible than normal hearts to stress-induced cell death because of a deficiency of a compound called cyclic guanosine monophosphate, or cGMP.

Christine Des Rosiers and colleagues found the hearts of DMD mice treated with Viagra showed much less damage than those of untreated mice, while Summit Corp. researchers found the utrophin-stimulating compound C1100 increased strength in DMD mice.

Sildenafil and related medications, which have U.S. Food and Drug Administration approval to treat erectile dysfunction, as well as pulmonary hypertension, increase cGMP by blocking the enzyme that normally breaks it down. Increased levels of cGMP result in dilation of blood vessels, including the coronary arteries.

DMD-affected mice treated with sildenafil had 44 percent less damage to heart-muscle cells than did untreated mice when their hearts were stressed with a drug known to increase cardiac workload.

The researchers say their findings demonstrate that enhancing signaling by cGMP in dystrophin-deficient hearts improves cardiac contraction and energy production and helps the membranes surrounding cardiac muscle cells resist tearing under stress.

They note that treatment with sildenafil and similar medications, which already exist, “constitutes a potential clinical avenue for treatment of the dystrophin-related cardiomyopathies.” However, currently there is no clinical data to support the use of these drugs in people.

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Utrophin-stimulating compound improves strength, endurance in mice

An experimental compound that stimulates production of the muscle protein utrophin increased strength in dystrophin-deficient mice with a disease resembling Duchenne muscular dystrophy (DMD).

The compound, called SMT C1100, is made by Summit Corp. of Oxford, United Kingdom. When combined with a corticosteroid (prednisone-like medication), it reduced muscle fatigue during exercise.

The findings were first presented at the New Directions in Muscle Biology and Diseases conference held in New Orleans April 27-30. The company says it plans to begin phase 1 clinical trials in 2009.

SMT C1100 is a small molecule designed to increase production of utrophin, a protein that at least partially compensates for the lack of functional dystrophin that characterizes DMD and Becker muscular dystrophy (BMD).

The major advantages of the utrophin-stimulating drug over some of the other strategies being developed for DMD and BMD are that the drug is oral; it has the potential to be effective in a wide range of patients; and, since people with DMD and BMD already make normal utrophin, it’s highly unlikely to cause an unwanted immune response.

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Myotilin protein may be a viable therapeutic target in LGMD1A

Findings in a study published in the May issue of Muscle & Nerve show overproduction of the protein myotilin worsens the symptoms of type 1A limb-girdle muscular dystrophy (LGMD1A) in mice.

The myotilin gene, located on chromosome 5, carries instructions for the large myotilin protein found in the Z disc — the structure that anchors the thick and thin filaments that slide together to cause muscle to contract. Defects (mutations) in the myotilin gene lead to the production of abnormal (mutated) myotilin protein, which causes disorganization in the muscle fibers and is the underlying cause of LGMD1A.

MDA grantee Michael Hauser at the Center for Human Genetics at Duke University in Durham, N.C., and colleagues, examined the severity of muscle degeneration and conducted microscopic analysis of muscle fibers in mice bred to produce mutated myotilin alone or mutated myotilin and higher-than-average levels of normal myotilin.

They found the mice making mutant myotilin had signs of LGMD1A, but those making increased levels of normal myotilin in addition to the mutated protein had increased severity of symptoms. These included earlier onset and a greater involvement of muscles less affected in mice that produced only mutant myotilin.

The researchers indicated that a “knockdown” approach, in which the amounts of both abnormal and normal myotilin are reduced, might be an effective therapeutic strategy for LGMD1A, although Hauser suggests more work may be needed in developing highly efficient knockdown methods, and “it may turn out that effective therapy will require a combination of several different methods at once.”

Calling the mouse experiment “a big step forward in understanding the mechanism in LGMD1A,” Hauser noted, “This improved understanding of mechanism is an important part of designing effective therapies for any muscular dystrophy.”

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ID of protein that prevents myelin formation could have implications for CMT treatment

Scientists in the United Kingdom and Italy have found that a protein called c-jun keeps cells associated with nerve fibers from maturing and producing myelin, a fatty sheath that insulates the fibers and speeds transmission of signals to and from nerve cells.

Kristjan Jessen at University College London and colleagues, who reported their findings May 19 in the Journal of Cell Biology, say it’s likely the normal role of c-jun is to push myelin-making cells, known as Schwann cells, back to a more primitive state after nerves are injured. Schwann cells normally return to this earlier stage of development after injury, they note, as part of the process of nerve-fiber repair and regeneration.

However, in Charcot-Marie-Tooth disease (CMT), abnormal loss of myelination occurs, slowing nerve signals and leading to disability. Several forms of CMT, including the relatively common CMT1A and CMT1B, as well as other diseases, are characterized by abnormalities in myelination of nerve fibers.

The investigators say it will be important to determine whether c-jun is involved in causing these abnormalities. If so, they say, targeting c-jun might open new avenues for treatment.

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