Chemical reversal of the RNA gain of function in myotonic dystrophy

Myotonic dystrophy type 1 (DM1) is one of a number of microsatellite expansion diseases in which the causative mutation is an aberrant expansion of a 3-nt repeat (1). The DM1 mutation was identified in 1992, and by 2001 it was established that the primary cause of pathogenesis is toxicity of the repeat-containing RNA transcribed from the expanded allele. One mechanism by which the RNA induces pathogenesis is through direct binding and sequestration of the RNA binding protein, muscleblind-like 1 (MBNL1). MBNL1 regulates a subset of alternative splicing events, and its depletion from the nucleoplasm results in misregulation of these events, causing features of the disease (2). In this issue of PNAS, Warf et al. (3) screened a relatively small number of nucleic acid binding compounds to identify those that could disrupt MBNL1–RNA interactions. The results add to the growing list of agents targeting the repeat-containing RNA of DM1 and are the first small molecules to show promising reversal of splicing defects in a DM1 mouse model.

DM1 is caused by a CTG expansion in the 3′ UTR of the DMPK gene. Unaffected individuals have <38 CTG repeats, whereas expansions associated with DM1 range from 80 to >2,500 repeats. Repeat length correlates directly with disease severity and inversely with the age of onset. DM1 is dominantly inherited and multisystemic; the primary causes of mortality and morbidity are progressive muscular dystrophy, cardiac-related sudden death, and CNS dysfunction (4). Therefore, systemic delivery of therapeutic compounds is a …

¹E-mail: tcooper{at}bcm.tmc.edu