Oral administration of erythromycin decreases RNA toxicity in myotonic dystrophy

Annals of Clinical and Translational Neurology
Masayuki NakamoriMasanori P Takahashi

Abstract

Myotonic dystrophy type 1 (DM1) is caused by the expansion of a CTG repeat in the 3' untranslated region of DMPK. The transcripts containing an expanded CUG repeat (CUG (exp)) result in a toxic gain-of-function by forming ribonuclear foci that sequester the alternative splicing factor muscleblind-like 1 (MBNL1). Although several small molecules reportedly ameliorate RNA toxicity, none are ready for clinical use because of the lack of safety data. Here, we undertook a drug-repositioning screen to identify a safe and effective small molecule for upcoming clinical trials of DM1. We examined the potency of small molecules in inhibiting the interaction between CUG (exp) and MBNL1 by in vitro sequestration and fluorescent titration assays. We studied the effect of lead compounds in DM1 model cells by evaluating foci reduction and splicing rescue. We also tested their effects on missplicing and myotonia in DM1 model mice. Of the 20 FDA-approved small molecules tested, erythromycin showed the highest affinity to CUG (exp) and a capacity to inhibit its binding to MBNL1. Erythromycin decreased foci formation and rescued missplicing in DM1 cell models. Both systemic and oral administration of erythromycin in the DM1 model mice showed spli...Continue Reading

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Datasets Mentioned

BETA
GM03989
GM07492

Methods Mentioned

BETA
antisense oligonucleotides
Assay
PCR
Fluorescence
electrophoretic mobility shift
fluorescence titration assay
transgenic
fluorescence titration

Software Mentioned

DiscoveRx PathHunter ProLabel
ImageQuant

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