Muscle Contractions In Mouse Model Of Muscular Dystrophy Reversed By UF Scientis

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Muscle Contractions In Mouse Model Of Muscular Dystrophy Reversed By

UF Scientists

http://www.medicalnewstoday.com/medicalnews.php?newsid=47565

University of Florida scientists have used gene therapy to eliminate

disabling muscle contractions in a mouse model of the most common

form of adult-onset muscular dystrophy.

The inherited disorder, known as myotonic dystrophy, is found in one

of every 8,000 people and causes skeletal muscles to lose the ability

to relax once they contract.

" One of the principal manifestations of the disease is myotonia, or

muscle hyperexcitability, " said Maurice Swanson, Ph.D., the paper's

senior author and a professor of molecular genetics and microbiology

at UF's College of Medicine and the UF Genetics Institute. " So when

patients with myotonic dystrophy contract one of the muscles in their

arm, it's very difficult for them to release that contraction. "

The muscles progressively weaken and eventually waste away. The

disease also affects the heart muscle and is associated with

irregular heart rhythms that can lead to sudden death. It also can

result in cataracts, premature hair loss and mild to moderate mental

retardation.

The work, to be published this week in the Proceedings of the

National Academy of Sciences, builds on previous research at UF and

the University of Rochester School of Medicine and Dentistry that

revealed myotonic dystrophy is caused by malfunctioning genes that

block the action of key proteins in cells, including one known as the

muscleblind protein. These proteins, which help muscle and eye cells

mature, stick to warped copies of RNA molecules that build up in a

cell's nucleus and prevent the proteins from working properly.

In the current study, UF researchers used mice that carry the mutated

genes and develop the muscle problems characteristic of myotonic

dystrophy.

The scientists equipped the adeno-associated virus, or AAV-a safe and

widely used vector in gene therapy-to express extra copies of the

muscleblind protein. They then injected it into a muscle in the shin

in the mutant mice.

" We simply tried to correct some of problems that arise by flooding

the muscle with extra copies of the muscleblind protein, " Swanson

said. " We were able to correct the myotonia as early as four weeks

after injection, and at 23 weeks it was completely eliminated in the

muscle that was injected with AAV carrying this muscleblind protein. "

Another six mice were in the control group and received injections of

green fluorescent protein. Their muscle function did not improve.

In effect, patients with myotonic dystrophy retain many of the

newborn versions of all the proteins the body makes, Swanson said.

" We all know newborn muscle is very different than adult muscle, " he

said. " It's not just that adults have more muscle, but in adults,

proteins are being expressed that have changed between the time we

were newborns to the time we became adults. That transition to adult

proteins is prevented in myotonic dystrophy.

" Basically, these fetal forms of proteins that are expressed during

embryonic and neonatal life are present in adult myotonic dystrophy

patients and are incompatible with adult function of muscle, " he

added. " The reason that's true is muscleblind proteins are factors

that regulate this transition from newborn to adult proteins. The

muscleblind proteins' responsibility in cells is to make that

transition, to force the production of the adult proteins. "

In the next phase of the research, the scientists plan to inject the

gene therapy solution directly into the bloodstream.

" Myotonic dystrophy patients want all their muscles corrected, not

just one, " Swanson said. " One way to get around this problem is to

try systemic injections in this mouse model. We'd like to correct all

abnormal muscle contractions, not just in a specific muscle group.

" About 30 percent of myotonic dystrophy patients succumb to heart

problems, so theoretically systemic injections might also prevent

that, " he added.

Scientists eventually hope to find out whether correcting myotonia

early by restoring normal levels of functioning muscleblind protein

might prevent at least some of the muscle loss that characterizes the

adult-onset disease. But researchers are years away from testing the

gene therapy approach in people.

" Basically we have to make sure everything works correctly in mice

before we can proceed to human trials, " Swanson said. " That's a long

way off. "

Tapscott, M.D., Ph.D., a professor of neurology at the

University of Washington and a researcher at the Center on Human

Development and Disability at the Fred Hutchinson Cancer Research

Center in Seattle, called the findings " an important advance for

developing therapies for myotonic dystrophy. "

" The demonstration that muscleblind can be delivered to diseased

muscle and reverse the disease process in this mouse model achieves

an important landmark step that will inform future preclinical and,

ultimately, clinical studies in myotonic dystrophy, " he said.

Until now it was difficult to even contemplate a way of treating the

disease because it is extraordinarily complex, said Day, M.D.,

Ph.D., a professor of neurology at the University of Minnesota School

of Medicine, but the research has identified a common element that

underlies many of the disease's different features.

" A means of delivering the treatment to humans still needs to be

developed, but this now provides proof of principle that the approach

is effective in this important mouse model, " Day said. " For the first

time this really raises the hope of people suffering from this common

form of muscular dystrophy that a treatment could someday be

forthcoming that will address the many serious components of this

disease. "