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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.

Author information

1
Department of Biochemistry & Molecular Biology, Center for NeuroGenetics, College of Medicine, University of Florida, Gainesville, Florida, 32610, USA.
2
Department of Medicinal Chemistry, Center for Natural Products Drug Discovery and Development, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA.
3
Department of Neurology, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
4
Department of Biological Sciences, RNA Institute, College of Arts and Sciences, University at Albany-SUNY, Albany, New York, 12222, USA.

Abstract

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.

KEYWORDS:

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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