2. Academic Validation
  3. Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy

Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy

  • Sci Rep. 2017 May 30:7:46126. doi: 10.1038/srep46126.
Yukiya Sako 1,  Kensuke Ninomiya 1,  Yukiko Okuno 2,  Masayasu Toyomoto 1,  Atsushi Nishida 3,  Yuka Koike 1,  Kenji Ohe 1,  Isao Kii 1,  Suguru Yoshida 4,  Naohiro Hashimoto 5,  Takamitsu Hosoya 4,  Masafumi Matsuo 3,  Masatoshi Hagiwara 1
Affiliations

Affiliations

  • 1 Department of Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 2 Medical Research Support Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 3 Department of Medical Rehabilitation, Faculty of Rehabilitation, Kobegakuin University, Kobe, Japan.
  • 4 Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
  • 5 Department of Regenerative Medicine, National Center for Geriatrics and Gerontology, Oobu, Japan.
PMID: 28555643 DOI: 10.1038/srep46126
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-122631
    CLK1抑制剂
    CDK
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