Open AccessOral administration of erythromycin decreases RNA toxicity in myotonic dystrophy
Author(s) -
Nakamori Masayuki,
Taylor Katarzyna,
Mochizuki Hideki,
Sobczak Krzysztof,
Takahashi Masanori P.
Publication year - 2016
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.271
Subject(s) - myotonic dystrophy , rna splicing , myotonia , medicine , pharmacology , tolerability , toxicity , in vivo , trinucleotide repeat expansion , erythromycin , rna , cancer research , biology , biochemistry , antibiotics , genetics , adverse effect , gene , allele
Objective Myotonic dystrophy type 1 ( DM 1) 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 ( MBNL 1). 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 DM 1. Methods We examined the potency of small molecules in inhibiting the interaction between CUG exp and MBNL 1 by in vitro sequestration and fluorescent titration assays. We studied the effect of lead compounds in DM 1 model cells by evaluating foci reduction and splicing rescue. We also tested their effects on missplicing and myotonia in DM 1 model mice. Results Of the 20 FDA ‐approved small molecules tested, erythromycin showed the highest affinity to CUG exp and a capacity to inhibit its binding to MBNL 1. Erythromycin decreased foci formation and rescued missplicing in DM 1 cell models. Both systemic and oral administration of erythromycin in the DM 1 model mice showed splicing reversal and improvement of myotonia with no toxicity. Long‐term oral administration of erythromycin at the dose used in humans also improved the splicing abnormality in the DM 1 model mice. Interpretation Oral erythromycin treatment, which has been widely used in humans with excellent tolerability, may be a promising therapy for DM 1.