Blocking Toxic RNA Diminishes Cell and Organ Damage in Muscular Dystrophy

Drug developers have combined computer screening with in vitro and in vivo bioactivity assays to identify a family of small molecules that could bind to and inactivate a toxic form of RNA, which causes the muscle and organ damage in adult-onset muscular dystrophy.

Myotonic dystrophy type 1 (DM1) is a triplet repeating disorder caused by expanded CTG (cytosine-thymine-guanine) repeats in the 3’ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The transcribed repeats fold into an RNA hairpin with multiple copies of a 5’CUG (cytosine-uracil-guanine) motif that binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1). Inactivation of MBNL1 by expanded r(CUG) repeats causes splicing defects in a subset of pre-mRNAs including the insulin receptor, the muscle-specific chloride ion channel, cardiac troponin T (cTNT), and others.

Protein splicing abnormalities caused by the inactivation of MBNL1 cause symptoms that can include wasting of the muscles and other muscle problems, cataracts, heart defects, and hormone changes.

To reverse r(CUG) damage investigators at the Scripps Research Institute (Jupiter, FL, USA) used an advanced computer screening technique combined with bioactivity studies in cell cultures and animal models to design multivalent ligands capable of binding multiple copies of the r(CUG)motif.

The investigators reported the details of these studies in the February 2, 2012, online edition of Journal of the American Chemical Society, and in the February 14, 2012, online edition of the journal ACS Chemical Biology. They reported that the designed compounds significantly improved DM1-associated defects including improvement of translational and pre-mRNA splicing defects and the disruption of nuclear foci in both cellular and animal models.

“Our compounds attack the root cause of the disease and they improve defects in animal models,” said contributing author Dr. Matthew Disney, associate professor of chemistry at the Scripps Research Institute. “This represents a significant advance in rational design of compounds targeting RNA. The work not only opens up potential therapies for this type of muscular dystrophy, but also paves the way for RNA-targeted therapeutics in general.”

“There are limitless RNA targets involved in disease; the question is how to find small molecules that bind to them,” said Dr. Disney. “We have answered that question by rationally designing these compounds that target this RNA. There is no reason that other bioactive small molecules targeting other RNAs could not be developed using a similar approach.”

Related Links:
Scripps Research Institute