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Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy
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Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy
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Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy
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Journal Article
Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy
2017
Overview
Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease. Various attempts are underway to convert severe DMD to a milder phenotype by modulating the splicing of the
dystrophin
gene and restoring its expression. In our previous study, we reported TG003, an inhibitor of CDC2-like kinase 1 (CLK1), as a splice-modifying compound for exon-skipping therapy; however, its metabolically unstable feature hinders clinical application. Here, we show an orally available inhibitor of CLK1, named TG693, which promoted the skipping of the endogenous mutated exon 31 in DMD patient-derived cells and increased the production of the functional exon 31-skipped dystrophin protein. Oral administration of TG693 to mice inhibited the phosphorylation of serine/arginine-rich proteins, which are the substrates of CLK1, and modulated pre-mRNA splicing in the skeletal muscle. Thus, TG693 is a splicing modulator for the mutated exon 31 of the dystrophin gene
in vivo
, possibly possessing therapeutic potential for DMD patients.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 64/60
/ 82/29
/ 82/58
/ 96/109
/ Animals
/ Arginine
/ Duchenne's muscular dystrophy
/ Enzyme Inhibitors - administration & dosage
/ Enzyme Inhibitors - chemistry
/ Enzyme Inhibitors - pharmacokinetics
/ Enzyme Inhibitors - therapeutic use
/ Humanities and Social Sciences
/ Humans
/ Male
/ Mice
/ mRNA
/ Muscle, Skeletal - metabolism
/ Muscular Dystrophy, Duchenne - drug therapy
/ Muscular Dystrophy, Duchenne - genetics
/ Protein-Serine-Threonine Kinases - antagonists & inhibitors
/ Protein-Serine-Threonine Kinases - metabolism
/ Protein-Tyrosine Kinases - antagonists & inhibitors
/ Protein-Tyrosine Kinases - metabolism
/ Rodents
/ Science
/ Serine
/ Splicing
/ Thiazoles - administration & dosage
