MMD Research: 'Bright' Prospect

Researchers at the University of Rochester (N.Y.) Wellstone Muscular Dystrophy Cooperative Research Center have identified a compound that has the potential to be developed into a treatment for type 1 myotonic dystrophy (MMD1, or DM1).

The compound, dubbed CAG25, is an "antisense oligonucleotide," a type of construct that's been used to block disease-causing genetic instructions in laboratory experiments and human trials in other diseases.

In the current experiments, the antisense oligonucleotide was given to mice with a disease resembling human MMD1 to see whether it could counteract some of the effects of abnormal genetic instructions in this disease.

Charles Thornton (pictured above), who co-directs the MDA clinic at the University of Rochester Medical Center, coordinated the research team, which published its findings July 17, 2009, in the journal Science.

The Wellstone Center at the University of Rochester has had funding from MDA and the National Institutes of Health.

"Myotonic dystrophy doesn't follow the usual rules of genetic conditions," Thornton said. "This work shows that we can take our new knowledge about the disease and use it to design customized treatments. The results in lab testing were better than I could have hoped, but these are still early steps."

About type 1 myotonic dystrophy

In humans, MMD1 is caused by an expanded section of DNA in a gene on chromosome 19. The expanded DNA results in synthesis of longer-than-normal strands of RNA, a close relative of DNA. The expanded RNA sections are made of repeated sequences of the chemicals cytosine, uracil and guanine and are called "CUG repeats."

The long RNA pieces become trapped in the nuclei of muscle fibers, and protein molecules in each nucleus become stuck to the CUG repeats.

This causes disruptions in the muscle fibers, including abnormalities in the structure and location of chloride ion channels, which regulate passage of chloride into and out of the fibers. When the ion channels are abnormal, myotonia, the inability to relax muscles after use, results.

MMD1 also can involve cardiac, gastrointestinal, ocular and cognitive abnormalities.

The mice used in these experiments had a disease resembling human MMD1 that was caused by expanded CUG repeats in a different gene from the one harboring the expansion in humans with the disease. However, the molecular effects are similar.

The mice have extra-long RNA strands that can't leave the nuclei of muscle fibers. As in the human disease, protein molecules are stuck to these pieces of RNA, and chloride channels are abnormal. The mice also have myotonia.

About these experiments

The hypothesis Thornton's research group set out to test was whether releasing proteins stuck to long strands of RNA would allow the proteins to resume their normal activities and improve symptoms in mice with an MMD1-like disease.

Cell Diagram
In MMD1, extra-long strands of genetic material called RNA trap a protein called MBNL1. In mouse muscles, CAG25 freed MBNL1 from this trap, apparently improving some aspects of muscle function.

These mice were given injections of CAG25 into one leg muscle and injections of an inactive substance into the corresponding muscle on the other leg. Researchers interpreting the results of the experiments didn't know until later which legs had received CAG25.

The muscles treated with CAG25 displayed several improvements in molecular structure and function, compared to the untreated muscles.

Much of the expanded RNA was able to leave the nucleus and relocate properly to the muscle-fiber cytoplasm, the main part of the fiber. A protein called MBNL that becomes stuck to the CUG repeats in human and mouse MMD1 was freed from them.

The structure and location of the chloride ion channels were normalized, and myotonia decreased in the CAG25-treated muscles.

Future directions

"What we have now is proof of concept that this general approach for treating myotonic dystrophy is potentially effective," Thornton said, noting that results of the new study should encourage researchers to improve and refine the strategy.

But, he noted, two major challenges remain. One is finding a way to deliver antisense oligonucleotides like CAG25 to all the muscles in the body, instead of injecting single muscles at a time. "This does not seem to be insurmountable," Thornton said, citing the work of other scientists.

The second major challenge is to determine whether the therapeutic antisense oligonucleotides cause serious side effects. If they do, Thornton said, other kinds of drugs that can release stuck proteins or allow muscle cells to produce more of these needed proteins could potentially be developed.

"It's too soon to predict which of these approaches ultimately will succeed," Thornton said, "but the prospects for developing treatments for myotonic dystrophy are looking bright."

Get involved

If you or your child has type 1 or type 2 myotonic dystrophy, you're encouraged to join the National Registry of Myotonic Dystrophy and FSHD Patients and Family Members.

This registry, based at the University of Rochester, was developed to help people with myotonic dystrophy or facioscapulohumeral muscular dystrophy participate in research on their disease and help investigators connect with them.

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