Combination Treatment of Erythromycin and Furamidine
Provides Additive and Synergistic Rescue of Mis-splicing in Myotonic
Dystrophy Type 1 Models
Posted on 2019-07-23 - 00:29
Myotonic dystrophy type 1 (DM1) is
a multisystemic 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 multistep pathogenic mechanism, combination therapies targeting
multiple 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, the 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.
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Jenquin, Jana R.; Yang, Hongfen; W. Huigens III, Robert; Nakamori, Masayuki; Berglund, J. Andrew (2019). Combination Treatment of Erythromycin and Furamidine
Provides Additive and Synergistic Rescue of Mis-splicing in Myotonic
Dystrophy Type 1 Models. ACS Publications. Collection. https://doi.org/10.1021/acsptsci.9b00020