Direct Reprogramming of Human DMD Fibroblasts into Myotubes for In Vitro Evaluation of Antisense-Mediated Exon Skipping and Exons 45-55 Skipping Accompanied by Rescue of Dystrophin Expression

Methods in Molecular Biology
Joshua J A LeeToshifumi Yokota

Abstract

Antisense oligonucleotide-mediated exon skipping is a promising therapeutic approach for the treatment of various genetic diseases and a therapy which has gained significant traction in recent years following FDA approval of new antisense-based drugs. Exon skipping for Duchenne muscular dystrophy (DMD) works by modulating dystrophin pre-mRNA splicing, preventing incorporation of frame-disrupting exons into the final mRNA product while maintaining the open reading frame, to produce a shortened-yet-functional protein as seen in milder Becker muscular dystrophy (BMD) patients. Exons 45-55 skipping in dystrophin is potentially applicable to approximately 47% of DMD patients because many mutations occur within this "mutation hotspot." In addition, patients naturally harboring a dystrophin exons 45-55 in-frame deletion mutation have an asymptomatic or exceptionally mild phenotype compared to shorter in-frame deletion mutations in this region. As such, exons 45-55 skipping could transform the DMD phenotype into an asymptomatic or very mild BMD phenotype and rescue nearly a half of DMD patients. In addition, this strategy is potentially applicable to some BMD patients as well, who have in-frame deletion mutations in this region. As the...Continue Reading

Citations

Dec 14, 2018·Journal of Personalized Medicine·Yusuke EchigoyaToshifumi Yokota
Apr 14, 2020·Proceedings of the Japan Academy. Series B, Physical and Biological Sciences·Kenichi Horisawa, Atsushi Suzuki
Sep 19, 2020·The Journal of Clinical Investigation·Stefano BiressiThomas A Rando
Apr 20, 2021·Molecular Therapy. Nucleic Acids·Xi XiangYonglun Luo

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