Scientists Uncover Most Detailed Picture Yet of Muscular Dystrophy Defect, Then Design Targeted New Drug Candidates

Scientists from The Scripps Research Institute (TRSI) have revealed an atomic-level view of a genetic defect that causes a form of muscular dystrophy, myotonic dystrophy type 2, and have used this information to design drug candidates with potential to counter those defects—and reverse the disease. “This the first time the structure of the RNA defect that causes this disease has been determined,” said TSRI Associate Professor Matthew Disney, who led the study. “Based on these results, we designed compounds that, even in small amounts, significantly improve disease-associated defects in treated cells.” Myotonic dystrophy type 2 is a relatively rare form of muscular dystrophy that is somewhat milder than myotonic dystrophy type 1, the most common adult-onset form of the disease. Both types of myotonic dystrophy are inherited disorders that involve progressive muscle wasting and weakness, and both are caused by a type of genetic defect known as an “RNA repeat expansion,” a series of nucleotides repeated more times than normal in an individual’s genetic code. The repeat binds to the protein MBNL1, rendering it inactive and resulting in RNA splicing abnormalities—which lead to the disease. Many other researchers had tried to find the atomic-level structure of the myotonic dystrophy 2 repeat, but had run into technical difficulties. In a technique called X-ray crystallography, which is used to find detailed structural information, scientists manipulate a molecule so that a crystal forms. This crystal is then placed in a beam of X-rays, which diffract when they strike the atoms in the crystal. Based on the pattern of diffraction, scientists can then reconstruct the shape of the original molecule.
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