Antisense-mediated exon skipping: A versatile tool with therapeutic and research applications

  1. Annemieke Aartsma-Rus and
  2. Gert-Jan B. van Ommen
  1. DMD genetic therapy group, Department of Human Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands

Abstract

Antisense-mediated modulation of splicing is one of the few fields where antisense oligonucleotides (AONs) have been able to live up to their expectations. In this approach, AONs are implemented to restore cryptic splicing, to change levels of alternatively spliced genes, or, in case of Duchenne muscular dystrophy (DMD), to skip an exon in order to restore a disrupted reading frame. The latter allows the generation of internally deleted, but largely functional, dystrophin proteins and would convert a severe DMD into a milder Becker muscular dystrophy phenotype. In fact, exon skipping is currently one of the most promising therapeutic tools for DMD, and a successful first-in-man trial has recently been completed. In this review the applicability of exon skipping for DMD and other diseases is described. For DMD AONs have been designed for numerous exons, which has given us insight into their mode of action, splicing in general, and splicing of the DMD gene in particular. In addition, retrospective analysis resulted in guidelines for AON design for DMD and most likely other genes as well. This knowledge allows us to optimize therapeutic exon skipping, but also opens up a range of other applications for the exon skipping approach.

Keywords

Footnotes

  • Reprint requests to: Annemieke Aartsma-Rus, DMD genetic therapy group, Department of Human Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands; email: a.m.rus{at}lumc.nl; fax: 31-71-5268285.

  • Article published online ahead of print. Article and publication date are at http://www.rnajournal.org/cgi/doi/10.1261/rna.653607.

  • Freely available online through the open access option.

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