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."
Stephen 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 John 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."
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