Researchers from The Scripps Research Institute (TSRI), University of Texas Medical Branch (UTMB), and Northwestern University have revealed an atomic-level view of a genetic defect that causes a form of muscular dystrophy known as myotonic dystrophy type 2. This information is being used to design drug candidates to counteract those defects.
According to TSRI Associate Professor Matthew Disney, who led the study, “This is the first time the structure of the RNA defect that causes this disease has been determined. 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 milder form than type 1 and is a relatively rare form. Type 1 is the most common adult-onset form. Both types are inherited disorders that involve progressive muscle wasting and weakness. Both are caused by a genetic defect known as RNA repeat expansion. RNA repeat expansion is a series of nucleotides repeated more times than usual in the genetic code. The repeat binds to a protein known as MBNL1 rendering it inactive which results in RNA splicing problems.
Researchers have tried to determine the atomic-level structure of the myotonic dystrophy 2 repeat, but had technical difficulties in doing so. Once a molecule is isolated, researchers make a crystal form of it and use X-ray crystallography to see the structure of the molecule. Beams of X-rays diffract when they strike the atoms in the crystal. Based on a pattern of diffraction, researchers can then reconstruct the shape of the original molecule.
Technical difficulties involved an inability to crystallize the RNA. The Scripps Florida team took several years working on this issue and were able to engineer the RNA to have crystal contacts in different positions. This allowed the RNA to be crystallized and its structure to be revealed. Once researchers had the RNA structure and movement, they were able to design molecules to improve RNA function. The new findings have been confirmed with sophisticated computational models that demonstrate how the small molecules interact with and alter RNA structure over time. These predictive models matched what scientists found in the study that is to say that these new compounds bind to the repeat structure in a predictable and easily reproducible way, attacking the cause of the disease.
Jessica Childs-Disney of TSRI, who is the first author of the paper with Ilyas Yildirim of Northwestern University, notes, “We used a bottom-up approach, by first understanding how the small components of the RNA structure interact with small molecules. The fact that our compounds improve the defects shows that our unconventional approach works.”
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