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New Genetic Therapies for Muscular Dystrophies

Apr 30, 2007 6:00 PM

If Muscle Cells Can Learn to 'Skip,' Patients May Not Need Wheelchairs

You probably know someone who has muscular dystrophy. Perhaps he is your neighbor, a young father who uses a wheelchair. He might be your child's classmate, or a close family member. He could be your co-worker, with symptoms so slight that you don't even notice them.

"People with muscular dystrophies are all around us," said Kevin Flanigan, M.D., associate professor of neurology in the School of Medicine and a member of the Brain Institute at the University of Utah. "Not all muscular dystrophies result in patients using wheelchairs or losing their ability to work, or having their life expectancy shortened."

Although the different muscular dystrophies can afflict people at different times in life, with varying impact and severity, one fact remains true: the most common form--Duchenne Muscular Dystrophy (which primarily afflicts males, although females can carry the trait and pass it on to their children)--is fatal. Flanigan has dedicated his career to changing that.

This past academic year, his research has taken him to Paris, where he is spending a sabbatical sponsored by the Association Francaise contre les Myopathies. He is collaborating at the Insitut de Myologie to develop trials of genetic therapies for Duchenne Muscular Dystrophy (DMD) and the less-severe Becker Muscular Dystrophy (BMD). The most common muscular dystrophy, DMD typically arises in patients 3-5 years old, and progresses rapidly; patients eventually lose the ability to walk and, ultimately, to breathe. BMD produces symptoms similar to DMD, but they are less severe and tend to show up later in life.

Both disorders result from mutations in the gene-encoding dystrophin, a protein that helps maintain muscle shape, Flanigan explained. When dystrophin is altered or absent, muscle cells lose their structure and break down, resulting in muscle weakness and impaired movement that worsen with age. The specific type of dystrophin mutation determines the severity of the disorder--which is providing important clues for developing genetic therapies to treat both forms.

DMD-causing mutations prevent muscle cells from producing any dystrophin, by creating a so-called "frameshift" that impairs the cell's ability to read DNA instructions for making the protein. Flanigan likened the way a cell reads DNA to how we translate a series of letters into words and sentences.

"For example, most of us interpret the series of letters oneboyandhisdogsawthecat, as a sentence: One boy and his dog saw the cat," he said. "A cell's machinery interprets DNA sequences in similar three-letter 'words,' each of which specifies an amino acid. When strung together, the amino acids make up a protein.

"But removing the O in One shifts the 'frame' of our sentence, so now it reads, Neb oya ndh isd ogs awt hec at," he continued.

"Just as this sentence makes no sense to us, mutations that shift the frame of dystrophin's DNA instructions result in a nonsensical string of amino acids that bears no resemblance to the dystrophin protein. Without the protein, muscle cells can't maintain their proper function, producing the more severe DMD."

In contrast, mutations associated with the milder BMD allow muscle cells to make smaller pieces of dystrophin, but not the entire protein. Though far from perfect, these pieces perform some of the dystrophin protein's function, resulting in the less-severe muscular dystrophy.

With this in mind, researchers wondered if it would be possible to trick DMD muscle cells into skipping the frameshift to read just part of the correct DNA sentence correctly. "In other words: if we skipped the Ne in Neb oya ndh isd ogs awt hec at, we would read Boy and his dog saw the cat," he said. "While our grammar teacher might not approve, it gets the point across. Similarly, could an incomplete piece of dystrophin protein be better than none at all for muscles in people with DMD?"

Flanigan and his French collaborators are among several research groups testing ways to make skipping happen. They also are exploring another approach that involves gene therapy: delivering DNA containing the proper instructions directly into the body's muscle cells. "The challenge," he said, "is how can we safely deliver a gene to this enormous portion of the body--the skeletal muscle--and get that gene to express a protein?"

The best mechanism for delivery may be a virus, which has remarkable efficiency at getting into systems in our bodies. Now scientists have engineered viruses that can "infect" muscle cells with the correct gene, but contain no other harmful agents. Yet viral approaches must be handled with great care, because they introduce the risk of an immune response to the virus in which the gene is packaged. Therefore, researchers also are developing non-viral methods for gene transfer that will not trigger the immune system.

Flanigan and his collaborators plan to participate in clinical trials of several such genetic therapies. Study participants will be recruited through the United Dystrophinopathy Project, a seven-site program funded by the National Institutes of Health (NIH) to enroll patients for detailed genetic characterization and long-term follow-up. To date, the researchers have enrolled more than 700 subjects, including patients with DMD and BMD, and female carriers.

"These subjects make up a remarkable catalog of patients for clinical trials," noted Flanigan, principal investigator on the project. "We know exactly what their clinical state is, as well as exactly what their mutation is."

Read the complete article at Health Sciences Report

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