ExonSkipping

Exon skipping is a form of RNA processing in which an exon is deliberately excluded from the mature messenger RNA produced from a gene. It is a natural aspect of alternative splicing that can generate diverse protein isoforms from a single gene. Exon skipping can also be induced therapeutically to alter the protein product in a way that mitigates disease-causing mutations.

The process involves the spliceosome recognizing splice sites at exon–intron boundaries. By blocking these sites or nearby regulatory elements, the splicing machinery omits the targeted exon during mRNA maturation. Therapeutically, this is most often achieved with antisense oligonucleotides (ASOs) that bind pre-mRNA to mask splice signals or enhancers. By preventing correct recognition of an exon, the cell splices it out of the transcript. Skipping can restore the reading frame when a mutation would otherwise produce a nonfunctional protein, producing a shorter but potentially functional protein. Exon skipping can also remove deleterious protein domains. Common ASO chemistries include phosphorodiamidate morpholino oligomers (PMOs) and 2'-O-methyl phosphorothioate oligos, designed for stability and tissue delivery.

Clinical relevance has been most evident in Duchenne muscular dystrophy (DMD). In the United States, the FDA has approved an exon-skipping ASO (eteplirsen) for patients amenable to exon 51, with other exon targets under study. Exon skipping is being explored for additional genetic disorders and in research to develop genome-editing approaches that induce exon skipping at the DNA or RNA level. Natural exon skipping also contributes to proteome diversity across tissues and developmental stages.