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Staurosporine allows dystrophin expression by skipping of nonsense-encoding exon.
- Source :
-
Brain & development [Brain Dev] 2016 Sep; Vol. 38 (8), pp. 738-45. Date of Electronic Publication: 2016 Mar 25. - Publication Year :
- 2016
-
Abstract
- Background: Antisense oligonucleotides that induce exon skipping have been nominated as the most plausible treatment method for dystrophin expression in dystrophin-deficient Duchenne muscular dystrophy. Considering this therapeutic efficiency, small chemical compounds that can enable exon skipping have been highly awaited. In our previous report, a small chemical kinase inhibitor, TG003, was shown to enhance dystrophin expression by enhancing exon skipping.<br />Purpose: Staurosporine (STS), a small chemical broad kinase inhibitor, was examined for enhanced skipping of a nonsense-encoding dystrophin exon.<br />Methods: STS was added to culture medium of HeLa cells transfected with minigenes expressing wild-type or mutated exon 31 with c.4303G>T (p.Glu1435X), and the resulting mRNAs were analyzed by RT-PCR amplification. Dystrophin mRNA and protein were analyzed in muscle cells treated with STS by RT-PCR and western blotting, respectively.<br />Results: STS did not alter splicing of the wild-type minigene. In the mutated minigene, STS increased the exon 31-skipped product. A combination of STS and TG003 did not significantly increase the exon 31-skipped product. STS enhanced skipping of exon 4 of the CDC-like kinase 1 gene, whereas TG003 suppressed it. Two STS analogs with selective kinase inhibitory activity did not enhance the mutated exon 31 skipping. When immortalized muscle cells with c.4303G>T in the dystrophin gene were treated with STS, skipping of the mutated exon 31 and dystrophin expression was enhanced.<br />Conclusions: STS, a broad kinase inhibitor, was shown to enhance skipping of the mutated exon 31 and dystrophin expression, but selective kinase inhibitors did not.<br /> (Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1872-7131
- Volume :
- 38
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Brain & development
- Publication Type :
- Academic Journal
- Accession number :
- 27021413
- Full Text :
- https://doi.org/10.1016/j.braindev.2016.03.003