Nationwide Children's Podcast Probes Exon Skipping in DMD

A January 2012 podcast from Nationwide Children's Hospital in Columbus, Ohio, explores the potential of a strategy called exon skipping as a treatment for Duchenne muscular dystrophy (DMD).

The podcast, which runs approximately 12 minutes, is part of a Nationwide Children's series called "This Month in Muscular Dystrophy."

It features MDA research grantee Stephen Wilton, head of the Molecular Genetic Therapies Group at the University of Western Australia's Centre for Neuromuscular and Neurological Disorders. Wilton is interviewed by Kevin Flanigan, a neurologist and neuromuscular disease researcher at Nationwide who also has received MDA support.

Exon skipping changes final genetic instructions

Wilton opens the podcast by explaining that genes are composed of exons, which directly code for proteins, and introns, which do not carry direct protein coding information and are spliced out of the final genetic message (RNA) for a protein. Normally, exons are left in the final RNA, but they can be left out (skipped) because of a natural genetic mutation or because of human intervention such as exon skipping.

In both DMD and Becker muscular dystrophy (BMD), the muscle protein that's lacking is dystrophin. Mutations in the dystrophin gene can either be out-of-frame, leading to a complete lack of dystrophin protein production and to DMD; or in-frame, leading to production of shorter and partially functional dystrophin such as is made by people with BMD, a muscle disorder similar to DMD but with milder symptoms.

Wilton describes how the type of exon skipping his group is developing uses antisense compounds to target specific exons in the RNA for dystrophin. This type of targeting changes out-of-frame genetic instructions to in-frame instructions and, it is hoped, changes absent dystrophin production to adequate dystrophin production.

Skipping certain exons increases dystrophin levels in mice

Wilton and his colleagues published a scientific paper in June 2010 in Molecular Therapy showing that, in mice, skipping certain exons restores the reading frame and allows production of dystrophin.

In this paper, the investigators describe how mice missing exon 19 alone or exon 20 alone develop a muscle disease resembling DMD, but that mice treated with an antisense exon-skipping compound so that they're missing both exons 19 and 20 develop a BMD-like disease.

Similarly, they show how mice missing either exon 52 or 53 alone develop a DMD-like disorder, but mice treated with an exon-skipping compound that eliminates exons 52 and 53 develop a BMD-like disorder.

Compounds targeting exon 51 are in clinical trials

Two exon-skipping compounds, both of which target exon 51, are now in clinical trials for boys with DMD with certain dystrophin mutations. The goal of skipping exon 51 is to restore the reading frame for dystrophin in boys with out-of-frame mutations in nearby exons.

One compound is a product in development by GlaxoSmithKline, called GSK2402968. The other, being developed by AVI BioPharma, is called eteplirsen or AVI-4658.

Early-stage trials of both compounds have suggested that they can safely increase dystrophin production.

For details and contact information on trials of these experimental compounds, visit, and enter the name of the drug in the search box. As of Jan. 11, 2012, trials of eteplirsen and GSK2492968 are being conducted at Nationwide Children's but are not recruiting new participants.

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