Use of Pentamidine in Myotonic Dystrophy Models

Myotonic Dystrophy is characterized by 200–2000 CUG repeats in the 3’UTR of the DMPK gene—unaffected individuals have 5–35 CUG repeats.  The CUG repeats form a stem-loop and it’s been suggested that this is a gain-of-function mutation wherein the stem loop binds proteins in the cell so that the proteins are unavailable to perform their normal cellular functions. Muscle-blind splicing factor is one such sequestered protein. As a result, at least 23 pre-mRNAs have been identified as mis-spliced and at least 15 proteins have defects.
 
One hypothesis for guiding development of therapeutic agents is that a molecule that binds to the CUG repeats will free the sequestered proteins to perform their normal cellular functions. Research at UO has found that the compound pentamidine binds to CUG repeats around two times more strongly than endogenous muscle-blind targets and can rescue cell splicing defects in cells expressing 960 CUG repeats. 

Pentamidine has previously been FDA approved and has been used as a prophylactic and treatment for its antimicrobial activity. Ongoing research seeks to find compounds based on pentamidine that will also exhibit CUG-repeat-binding activity.