The structural basis of myotonic dystrophy from the crystal structure of CUG repeats,

Therapies for debilitating muscle diseases

1 September 2011

A number of small, easy-to-synthesise molecules may offer hope to people affected by myotonic dystrophy.

Myotonic dystrophy type two (DM2) is an incurable disease characterised by muscle pain, weakness and delayed relaxation. Patients experience difficulties when performing routine tasks such as standing up from a seated position or relaxing their grip on objects. DM2 is caused by a mutation in one of the more than 1,000 genes on human chromosome 3. An expansion of a nucleotide repeat in this gene leads to the production of an altered form of its RNA transcripts, the messengers that normally carry genetic information from DNA templates on chromosomes to proteins. These altered transcripts, however, bind to and inhibit the activities of muscleblind-like (MBNL) proteins in cells, causing the clinical features of DM2.

Recent research efforts have focused on developing small molecules, or ligands, to disrupt the interaction between the abnormal RNA transcripts and MBNL proteins, thus treating DM2. There are several challenges to this approach. The RNA transcripts do not exist as isolated, linear structures in cells. Instead, they fold up and form secondary structures. These structures thus have to be taken into account when designing small molecules. However, the secondary structures formed by the altered transcripts in DM2 are currently unknown. Another challenge is the selectivity of the ligands – they should interact only with the target transcripts and not bind to other transcripts or proteins in cells.

In a recent issue of Nucleic Acids Research, a group at the University of Illinois published an article about the development of a series of small molecules targeting the pathogenic transcripts produced in DM2. Based on existing knowledge on the interaction between certain chemical groups and specific nucleotide mismatches on RNA transcripts. The group designed and synthesized a number of ligands possessing similar chemical motifs. Some of the ligands were found to interact with the RNA transcripts found in DM2. More important, two of the ligands were able to inhibit the interaction between the transcripts and the MBNL1 proteins with high selectivity over other targets. These results suggest that these synthetic molecules can potentially be used as therapies for DM2.

Mr Chun-Ho Wong, one of the lead investigators of this project, commented “DM is still an incurable disease affecting lots of families worldwide. I hope our findings will help develop a cure for the disease.” Wong is a 2007 Croucher Scholar who is studying for his PhD in Professor Steven Zimmerman’s laboratory at the University of Illinois.

To view Chun-Ho Wong's personal Croucher profile, please click here