Myotonic Dystrophy (DM)

Research

The major focus in myotonic dystrophy (DM) research has been on the molecular underpinnings of the disease. To date, most of the work has been done using animal and cellular models of type 1 DM (DM1). However, many experts believe the findings from DM1 experiments will have implications for type 2 DM (DM2) as well.

In both these conditions, the underlying defect is an expansion of DNA. In DM1, it is the chemical sequence cytosine, thymine, guanine (CTG) in a gene on chromosome 19. In DM2, it is the chemical sequence CCTG in a gene on chromosome 3. (See Causes/Inheritance.)

During the normal process by which cells transcribe DNA into RNA, the abnormal expansion is likewise transcribed, resulting in a long, unruly strand of RNA that stays in the cell nucleus and forms a trap for various cellular proteins. For instance, the protein known as MBNL1, which has a crucial role in ensuring that other proteins are properly formed, is trapped in this toxic "web" of expanded RNA in both forms of the disease. As a result, another protein, CUGBP1, is upregulated. Consequently, processes such as RNA editing, translation, and stability are severely affected.¹

Most of the strategies aimed at treating the underlying causes of DM1 and DM2 aim to either destroy the expanded, toxic RNA in DM-affected cells or block the interactions between it and proteins.

Three DM researchers whose work is particularly promising are using these strategies:

• Thomas Cooper at Baylor College of Medicine in Houston is using molecules called antisense oligonucleotides to attract an enzyme that destroys toxic RNA and frees proteins such as MBNL1.
• Matthew Disney at Scripps Research Institute in Jupiter, Fla., is using small molecules designed in his laboratory to free proteins from web-like toxic RNA.
• Charles Thornton is using both antisense oligonucleotides and small molecules to either destroy toxic RNA or separate it from cellular proteins.

To learn more, read DM Research: Seeking to Free Proteins from a 'Toxic Web'.

In January 2013, MDA established a five-center clinical research network. The researchers in each center will work together to standardize methods of evaluating disease severity and will determine the best ways to assess whether experimental treatments are beneficial.

The DM centers are:

• California: Stanford University School of Medicine, Stanford; John Day, MD, PhD (director)
• Florida: University of Florida College of Medicine, Gainesville; Tetsuo Ashizawa, MD (director)
• Kansas: University of Kansas Medical Center Research Institute, Kansas City; Richard Barohn, MD (director)
• New York: University of Rochester Medical Center, Rochester; Charles Thornton, MD (director; network's overall principal investigator)
• Ohio: Ohio State University Medical Center, Columbus; John Kissel, MD (director)

References

1. Lee, J. E. & Cooper, T. A. Pathogenic mechanisms of myotonic dystrophy. Biochem. Soc. Trans. (2009). doi:10.1042/bst0371281