An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases

Methods in Molecular Biology
Merryl Rodrigues, Toshifumi Yokota

Abstract

Exon skipping is a therapeutic approach that is feasible for various genetic diseases and has been studied and developed for over two decades. This approach uses antisense oligonucleotides (AON) to modify the splicing of pre-mRNA to correct the mutation responsible for a disease, or to suppress a particular gene expression, as in allergic diseases. Antisense-mediated exon skipping is most extensively studied in Duchenne muscular dystrophy (DMD) and has developed from in vitro proof-of-concept studies to clinical trials targeting various single exons such as exon 45 (casimersen), exon 53 (NS-065/NCNP-01, golodirsen), and exon 51 (eteplirsen). Eteplirsen (brand name Exondys 51), is the first approved antisense therapy for DMD in the USA, and provides a treatment option for ~14% of all DMD patients, who are amenable to exon 51 skipping. Eteplirsen is granted accelerated approval and marketing authorization by the US Food and Drug Administration (FDA), on the condition that additional postapproval trials show clinical benefit. Permanent exon skipping achieved at the DNA level using clustered regularly interspaced short palindromic repeats (CRISPR) technology holds promise in current preclinical trials for DMD. In hopes of achieving...Continue Reading

Citations

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