The therapeutic potential of antisense-mediated exon skipping.
Antisense-mediated exon skipping is an approach that uses antisense oligonucleotides (AONs) to modulate splicing by hiding specific sites essential for exon inclusion from the splicing machinery. AONs that block aberrant splice sites can restore normal splicing, whereas AONs targeting alternative splice sites can switch splicing patterns from detrimental to beneficial isoforms or produce non-functional mRNAs that lead to gene knockdown. Furthermore, AONs have also been used to restore a disrupted reading frame, thereby generating semi-functional proteins instead of non-functional proteins. Proof-of-concept has been obtained for each of the above AON applications in vitro and for some applications in vivo. Antisense-mediated reading frame restoration is the most promising therapy for Duchenne muscular dystrophy. Data from a first clinical trial are encouraging and additional trials are ongoing or are expected to be initiated soon.
van Ommen
Gert-Jan
GJ
Leiden University Medical Center, Department of Human Genetics, Zone S4-P, PO Box 9600, 2300 RC Leiden, the Netherlands.
van Deutekom
Judith
J
Aartsma-Rus
Annemieke
A
D017398:Alternative Splicing; D002986:Clinical Trials as Topic; D005091:Exons; D005822:Genetic Vectors; D006801:Humans; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use
D016376:Oligonucleotides, Antisense