Precision Medicine through Antisense Oligonucleotide-Mediated Exon Skipping. (November 2018)

• Record Type: Journal Article
• Authors: Li, Dunhui; Mastaglia, Frank L.; Fletcher, Sue; Wilton, Steve D.
• Is Part Of: Trends in pharmacological sciences. Volume 39:Number 11(2018)
• Page Start: 982
• Page End: 994
• Publication Date: 2018-11
• Subjects: antisense oligonucleotides -- dispensable exons -- inherited rare diseases -- precision medicine -- therapeutic alternative splicing; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2018.09.001
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : Clinical implementation of two recently approved antisense RNA therapeutics – Exondys51 ® to treat Duchenne muscular dystrophy (Duchenne MD) and Spinraza ® as a treatment for spinal muscular atrophy (SMA) – highlights the therapeutic potential of antisense oligonucleotides (ASOs). As shown in the Duchenne and Becker cases, the identification and specific removal of 'dispensable' exons by exon-skipping ASOs could potentially bypass lethal mutations in other genes and bring clinical benefits to affected individuals carrying amenable mutations. In this review, we discuss the potential of therapeutic alternative splicing, with a particular focus on targeted exon skipping using Duchenne MD as an example, and speculate on new applications for other inherited rare diseases where redundant or dispensable exons may be amenable to exon-skipping ASO intervention as precision medicine. Highlights: It has been well established that some genes contain exons that can be omitted from the mature mRNA without seriously compromising gene function, while protein-truncating or missense mutations in those exons cause serious disease. Manipulation of dystrophin gene expression through redirecting pre-mRNA processing has given accelerated approval for the treatment of Duchenne muscular dystrophy. Antisense oligomer-induced exon skipping of a selected exon can allow a catastrophically defective dystrophin gene to synthesize a truncated but functional dystrophin isoform. Targeted exon skipping could be applied to many other inherited gene disorders if the disease-causing mutation is found to occur in an exon whose loss from the mature mRNA would not completely abrogate gene function. Since genomic deletions of an in-frame exon are rare in many genes, genotype–phenotype correlations are limited to infrequent splice site mutations that lead to exon skipping.