Scientists Reverse Muscular Dystrophy in Mice

THURSDAY July 16, 2009 -- Scientists have found a way to interfere with a stray genetic process critical in the development and progression of a major form of muscular dystrophy.

The strategy, described by researchers from the University of Rochester in the July 16 issue of Science, did alleviate symptoms of the debilitating disease and even, in some cases, reversed it but the successes have been seen only in mice so far.

"It's exciting. It's novel. It's very original but, to translate this into humans, there's still a long way to go," said Mendell Rimer, an assistant professor of neuroscience and experimental therapeutics at Texas A&M Health Science Center College of Medicine in College Station. "It's a step forward."

Another expert concurred.

"This is still early-stage preclinical work and therapy is not on the immediate horizon," said Dr. Valerie Cwik, senior vice president of research and medical director of the Muscular Dystrophy Association (MDA). "But this is proof of principle that you can impact the molecular underpinnings of myotonic dystrophy, which is an important step forward in trying to develop a therapy that affects so many systems in the body."

As Cwik explained, muscular dystrophy is "a multi-system disease" that can impact the brain, eyes, heart, gastrointestinal system and endocrine system, along with the muscles. "So trying to develop a therapy to target all of these systems or even several of them means you have to get at some of the underlying causes," she said.

According to the MDA, myotonic (muscle-stiffening) dystrophy is one of nine forms of muscular dystrophy, a group of genetic, degenerative and potentially disabling diseases which primarily affect voluntary muscles.

Myotonic dystrophy type 1 is the most common form of muscular dystrophy affecting adults. It is caused when a section of DNA is repeated on either chromosome 19 or chromosome 3, and results in muscles getting "locked" in the tensed state (myotonia) for long periods of time. Over time, patients experience progressive muscle wasting and weakness.

There is no cure for the disease nor are there many effective treatments. In fact, scientists are only now beginning to understand the mechanisms behind muscular dystrophy.

Several years ago, this same group of researchers showed that a genetic flaw leads to the overproduction of a certain type of messenger RNA (mRNA) in cells, which affects muscle control and other cellular functions.

The original defects in the DNA translate into expanded repeats in the RNA which then bind up various cellular proteins. These include one called "muscleblind," thought to be a key factor in myotonic dystrophy.

"Probably the main thing [the RNA] does is to act like a sponge and sop up some of the important proteins," said study senior author Dr. Charles Thornton, professor of neurology at the University of Rochester Medical Center and co-director of the University of Rochester Medical Center's Wellstone Muscular Dystrophy Cooperative Research Center.

This is the first time RNA has emerged as a culprit in a disease process, he said.

"We don't have to replace a bad gene. All we have to do is to keep this toxic RNA and these proteins from sticking to one another," continued Thornton. "In theory, if you could make that happen might you might actually make this disease go in reverse."

And the hypothesis panned out.

An "antisense morpholino oligonucleotide," a synthetic molecule, succeeded in pulling apart the RNA and the muscleblind proteins.

Using this molecule, "we neutralized a toxic RNA so it released the protein stuck on it," Thornton said.

A major challenge now will be to figure out a way to deliver the therapy to a person's entire body instead of just single muscles, he said.

"This only addresses the pathology in the muscle and the disease is more complex," Cwik said.

"There are a lot of potential issues especially regarding the delivery of the oligonucleotide," Rimer added. "They only test the effects of the oligonucleotide in one muscle, so if you want to apply this to humans you would have to find a way to deliver this to multiple muscles."

Also, said Cwik, it isn't clear how or even if this strategy would affect other proteins that also play a role in the disease.

The strategy does have the potential to affect the multiple systems targeted by muscular dystrophy, Cwik said. "It's working very early, very upstream so it has the potential to impact many aspects of the disease," she said. "But we haven't looked at this at all in humans yet."

More information

For more on the illness, head to the Muscular Dystrophy Association.

Posted: July 2009


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