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ACS Pharmacol Transl Sci. 2019 Aug 9;2(4):247-263. doi: 10.1021/acsptsci.9b00020. Epub 2019 Jul 17.

Combination Treatment of Erythromycin and Furamidine Provides Additive and Synergistic Rescue of Mis-Splicing in Myotonic Dystrophy Type 1 Models.

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Department of Biochemistry & Molecular Biology, Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, Florida, 32610, USA.
Department of Medicinal Chemistry, Center for Natural Products Drug Discovery and Development, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA.
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
Department of Biological Sciences, RNA Institute, College of Arts and Sciences, University at Albany-SUNY, Albany, New York, 12222, USA.


Myotonic dystrophy type 1 (DM1) is a multi-systemic disease that presents with clinical symptoms including myotonia, cardiac dysfunction and cognitive impairment. DM1 is caused by a CTG expansion in the 3' UTR of the DMPK gene. The transcribed expanded CUG repeat RNA sequester the muscleblind-like (MBNL) and up-regulate the CUG-BP Elav-like (CELF) families of RNA-binding proteins leading to global mis-regulation of RNA processing and altered gene expression. Currently, there are no disease-targeting treatments for DM1. Given the multi-step pathogenic mechanism, combination therapies targeting different aspects of the disease mechanism may be a viable therapeutic approach. Here, as proof-of-concept, we studied a combination of two previously characterized small molecules, erythromycin and furamidine, in two DM1 models. In DM1 patient-derived myotubes, rescue of mis-splicing was observed with little to no cell toxicity. In a DM1 mouse model, a combination of erythromycin and the prodrug of furamidine (pafuramidine), administered orally, displayed both additive and synergistic mis-splicing rescue. Gene expression was only modestly affected and over 40 % of the genes showing significant expression changes were rescued back toward WT expression levels. Further, the combination treatment partially rescued the myotonia phenotype in the DM1 mouse. This combination treatment showed a high degree of mis-splicing rescue coupled with low off-target gene expression changes. These results indicate that combination therapies are a promising therapeutic approach for DM1.


combination therapeutic; erythromycin; furamidine; myotonic dystrophy; toxic RNA

Conflict of interest statement

Conflict of Interest Disclosure: J. Andrew Berglund and the University of Oregon have patented diamidines for treating myotonic dystrophy (U.S. Patents 8463049 and 20130281462).

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