JUPITER, Fla.—Muscular dystrophy refers to a variety of inherited disorders characterized by musculoskeletal weakness, loss of muscle tissue and impeded motion. There are several subtypes of the disease, and patients diagnosed with one such subtype—myotonic dystrophy type 2—are starting the new year with some good news: a team of scientists at the Florida campus of The Scripps Research Institute have unveiled an atomic-level view of the genetic defect that causes this particular form of the disease. This model has allowed them to design drug candidates capable of targeting the defects and possibly reversing the disease. 
Myotonic dystrophy type 2 is a relatively rare form of the disease, and is less severe than myotonic dystrophy type 1, with symptoms that are generally mild and slow to progress, according to the Muscular Dystrophy Association website. Contrary to myotonic muscular dystrophy type 1, type 2 “does not appear to have a congenital-onset form and rarely begins in childhood,” the website adds. In this form of the disease, the first muscles to be affected are the proximal muscles, those near the core of the body, particularly around the hips. Both forms result from a genetic defect known as an RNA repeat expansion, in which a series of nucleotides is repeated more often than normal. That repeat binds to the MBNL1 protein, make it inactive and causing RNA splicing abnormalities, which in turn lead to the disease.
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Read MoreA common method of determining the atomic-level structure of molecules is X-ray crystallography, in which a molecule is manipulated until it forms a crystal, which is then placed in a beam of X-rays. Those rays diffract when they hit the atoms of the crystal, and based on the diffraction pattern, the original molecule’s shape can be reconstructed. Previous attempts to crystallize the RNA repeat have failed, but after years of effort, the Scripps team was able to engineer the RNA with crystal contacts in different positions, which finally enabled it to be crystallized.
“This the first time the structure of the RNA defect that causes this disease has been determined,” TSRI Associate Professor Matthew Disney, who led the study, said in a press release. “Based on these results, we designed compounds that, even in small amounts, significantly improve disease-associated defects in treated cells.”
With the structure of the RNA defect in hand, the Scripps scientists designed drug candidate molecules to improve RNA function, and computational models showed how the small molecules would interact with and change the RNA structure, making them capable of targeting the cause of myotonic dystrophy type 2.
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Read More“We used a bottom-up approach, by first understanding how the small components of the RNA structure interact with small molecules,” Jessica Childs-Disney of TSRI commented in a statement. Childs-Disney was first author of the paper with Ilyas Yildirim of Northwestern University. “The fact that our compounds improve the defects shows that our unconventional approach works.”
The study, “Myotonic Dystrophy Type 2 RNA: Structural Studies and Designed Small Molecules that Modulate RNA Function,” was published in an advance online issue of ACS Chemical Biology December 9. The study was supported by the National Institutes of Health (NIH), the Muscular Dystrophy Association, TSRI and the PS-OC Center of the NIH.
