Exon skipping

Genes are built of exons – pieces that must match their neighbours like a jigsaw. When a gene is read, the exons are assembled together in a process called splicing. When an exon is deleted this can stop the pieces joining and prevent cells producing dystrophin protein.

Becker muscular dystrophy – a more mild condition also caused by mutations in the dystrophin gene – is caused by deletions where the pieces can still be joined. This allows cells to produce a smaller protein that retains some function.

How does exon skipping work?

Exon skipping uses small drugs called antisense oligonucleotides to help cells skip over a specific exon during splicing. This allows cells to join a different set of exons together to produce a protein that is shorter than usual but may have some function.

Here, exon 50 has been deleted. By using a drug to skip over exon 51, the cell can join exon 49 and 51 to produce a shorter than normal dystrophin protein.

Who can exon skipping treat?

Exon skipping as a technology has the potential to treat the majority of those living with Duchenne. However, each exon to be skipped will require a separate drug. This means it will take a long time to develop treatments that can skip all 79 of the exons in the dystrophin gene.

Are exon skipping drugs available?

In the US, there are two exon skipping drugs approved. Exondys 51 (or eteplirsen) is a drug that skips exon 51 of the dystrophin gene and Vyondys 53 (or golodirsen) skips exon 53.

These drugs are not licensed in Europe or the UK, but Sarepta – the company that developed the drugs – is currently undertaking clinical trials to collect more information on the effectiveness of the drugs.

What are the challenges of exon skipping?

It is difficult to deliver antisense oligonucleotides to the muscle cells where it is needed. Researchers are currently working to develop AONs that preferentially target muscle and the heart.

The second challenge is that the effects are short lived. This means that exon skipping treatments have relied on regualr doses to maintain exon skipping in the muscles. Researchers hope to deliver different delivery methods that could overcome this challenge – potentially by using gene therapy approaches to allow muscle cells to produce the exon skipping drug internally.