Exon skipping

In molecular biology, exon skipping is a form of RNA splicing used to cause cells to “skip” over faulty or misaligned sections of genetic code, leading to a truncated but still functional protein despite the genetic mutation.

Exon skipping is used to restore the reading frame within a gene. Genes are the genetic instructions for creating a protein, and are composed of introns and exons. Exons are the sections of DNA that contain the instruction set for generating a protein; they are interspersed with non-coding regions called introns. The introns are later removed before the protein is made, leaving only the coding exon regions.

Splicing naturally occurs in pre-mRNA when introns are being removed to form mature-mRNA that consists solely of exons. Starting in the late 1990s, scientists realized they could take advantage of this naturally occurring cellular splicing to downplay genetic mutations into less harmful ones.

The mechanism behind exon skipping is a mutation specific antisense oligonucleotide (AON). An antisense oligonucleotide is a synthesized short nucleic acid polymer, typically fifty or fewer base pairs in length that will bind to the mutation site in the pre-messenger RNA, to induce exon skipping. The AON binds to the mutated exon, so that when the gene is then translated from the mature mRNA, it is “skipped” over, thus restoring the disrupted reading frame. This allows for the generation of an internally deleted, but largely functional protein.

Some mutations require exon skipping at multiple sites, sometimes adjacent to one another, in order to restore the reading frame. Multiple exon skipping has successfully been carried out using a combination of AONs that target multiple exons.

Exon skipping is being heavily researched for the treatment of Duchenne muscular dystrophy (DMD), where the muscular protein dystrophin is prematurely truncated, which leads to a non-functioning protein. Successful treatment by way of exon skipping could lead to a mostly functional dystrophin protein, and create a phenotype similar to the less severe Becker muscular dystrophy (BMD).

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