MILESTONES IN MEDICAL SCIENCE:

Turning off Muscular Dystrophy

August 2013

Myotonic dystrophy is an inherited disorder, the most common form of a group of conditions called muscular dystrophies that involve progressive muscle wasting and weakness. Myotonic dystrophy type 1 (MMD1) is the most common adult onset form of muscular dystrophy and is caused by a type of genetic RNA defect known as a "triplet repeat," a series of three nucleotides repeated more times than normal in an individual's genetic code.

For the first time, scientists from Scripps Florida, led by associate professor Matthew Disney, have identified small molecules that allow for complete control over the triplet repeat responsible for MMD1. These small molecules will enable scientists to investigate potential new therapies and study the long-term impact of the disease. "This is the first example I know of at all where someone can literally turn a disease on and off," said Dr. Disney.

The RNA defect that causes MMD1 is caused by an abnormally expanded gene, known as the DMPK gene. When the DMPK DNA is longer than normal, it causes a longer than normal RNA strand to be produced with a triplet repeat consisting of repeated chemical sequences known as CUG (cytosine, uracil, guanine).

Associate Professor Matthew Disney

The RNA can contain hundreds, or even thousands, of times the number of repeated CUG sequences seen in cells without the MMD1 mutation. The expanded RNA acts like a web, trapping important proteins and keeping them from their usual cellular jobs, which causes the RNA splicing abnormalities that result in MMD1.

To find drug candidates that act against the defect, Dr. Disney and his colleagues analyzed the results of a National Institutes of Health (NIH)-sponsored screen of more than 300,000 small molecules that inhibit a RNA-protein complex critical to MMD1 disease progression. The team divided the NIH hits into three groups—the first group bound RNA, the second bound protein, and a third group's mechanism was unclear. The researchers then studied the compounds by looking at their effect on human muscle tissue both with and without the defect.

The scientists identified one protein-binding compound that causes normal cells to behave like MMD1-affected cells, causing the disease to worsen in cells already affected by MMD1. They identified a second RNA-binding compound that reversed the process, making MMD1-affected cells act like normal cells and causing signs of the disease to go away.

The new compounds will serve as useful tools to study the disease on a molecular level. "In complex diseases, there are always unanticipated mechanisms," Dr. Disney noted. "Now that we can reverse the disease at will, we can study those aspects of it."

In addition, Dr. Disney said, with the new discovery scientists will be able to develop a greater understanding of how to control RNA splicing with small molecules. RNA splicing can cause a host of diseases that range from sickle-cell disease to cancer, yet prior to this study no tools were available to control specific RNA splicing.

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