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

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.

Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide

“…For this purpose, we used antisense oligonucleotides (AONs) to modulate splicing by hiding specific sites essential for exon inclusion from the splicing machinery, without modifying the genome. 32 The AONs used to modulate splicing are different from the oligonucleotides that are used to achieve downregulation of transcripts. The AONs should not activate RNase H, which would degrade the pre-mRNA, and should be able to compete with splicing factors for access to the pre-mRNA.…”

Dystrophin restoration in skeletal, heart and skin arrector pili smooth muscle of mdx mice by ZM2 NP–AON complexes

“…Others, however, such as drugs which induce stop-codon reversion 2 (PTC124) and antisense oligoribonucleotide (AON)-mediated exon skipping, [3][4][5] are already undergoing clinical trials. 6 These novel therapeutic options for DMD represent the first step toward a possible cure for this devastating disorder.…”

Clin d’œil du Dinosaure émérite

“…: seize ans pour aller de la paillasse au médicament 1 2 La stratégie du saut d'exon thérapeutique (SET) ciblant le transcrit primaire du gène DMD [1][2][3] a été imaginée il y a déjà 16 ans par G.J. van Ommen et son équipe [4].…”

“…L'agrément accordé à Eteplirsen : une décision de la FDA obtenue à l'arraché [7] Cette décision est intervenue le 19 septembre 2016 au terme d'une véritable bataille 3 entre d'une part les partisans des deux produits, c'est-à-dire les compagnies Sarepta Therapeutics et BioMarin, et les associations de malades, et d'autre part les détracteurs, c'est-à-dire les experts de la FDA chargés de statuer. Dans un premier temps, en janvier 2016, ceux-ci ont retoqué l'AON historique, présenté par Biomarin sous le nom de Kyndrisa ® , au motif d'une efficacité non convaincante (en termes de réexpression de la dystrophine) et d'une indéniable toxicité.…”

“…Ce verdict a entraîné l'abandon du projet par Biomarin avec les conséquences boursières que l'on imagine. Le dossier du produit concurrent, présenté par Sarepta Therapeutics sous le nom d'Exondys 51 ® a bénéficié d'un sursis à statuer, pendant lequel la FDA 3 Les journalistes anglo-saxons ont utilisé le terme de « bickering », en français chamailleries.…”