Research Briefs: DMD Exon Skipping

Clinical trials of two different exon-skipping compounds show encouraging results; Duchenne MD participants are being sought for new trials

Exon skipping for Duchenne MD is a strategy that uses chemicals called antisense oligonucleotides to cause cells to "skip" flawed sections of genetic instructions for making the muscle protein dystrophin, thereby allowing synthesis of a functional protein.
Article Highlights:
  • Complete results are now available of a phase 1 trial of exon-skipping compound PRO051/GSK2402968, which is designed for Duchenne MD that's caused by certain mutations.
  • A phase 1 trial of PRO051/GSK2402968 is open in Columbus, Ohio. Later-stage trials of this compound are under way outside the United States.
  • Screening for a phase 1 trial of the exon-skipping compound AVI4658 is under way in Columbus, Ohio. A recent phase 1-2 trial of AVI4658 in the United Kingdom showed positive results.
  • MDA continues to support preclinical development of exon skipping for DMD
by Margaret Wahl on March 29, 2011 - 11:42am

sClinical trials that use compounds called antisense oligonucleotides to cause skipping of exon 51 of the dystrophin gene in individuals with Duchenne muscular dystrophy (DMD) are moving forward in the United States and elsewhere.

Exon skipping for DMD is a strategy that coaxes muscle fibers to ignore, or "skip," the genetic instructions for certain parts of the dystrophin gene so that functional dystrophin protein can be made despite the presence of a genetic mutation.

MDA has been involved in preclinical development of exon skipping for many years and continues to fund research in this important area.

Below is a roundup of information about the progress of two exon-skipping compounds under development.

Complete results of PRO051/GSK2402968 trial now available

Complete and encouraging results have been released for a phase 1 trial of the exon-skipping compound PRO051/GSK2402968, in development by Prosensa and GlaxoSmithKline (GSK) for boys with DMD who can benefit from skipping exon 51 of the dystrophin gene.

The trial included 12 DMD-affected boys with specific dystrophin gene mutations and was conducted in Belgium and Sweden. Results showed that all trial participants produced the dystrophin protein, and there was an average increase of about 115 feet in the distance participants could walk in six minutes.

Results were published online March 23, 2011, in the New England Journal of Medicine. Encouraging preliminary results were first announced in April 2010 (see Progress in Exon Skipping for DMD).

During the first, five-week phase of the trial, the boys were divided into four groups of three, with each group receiving a higher dose of the experimental compound than the previous group. The second phase was a 12-week extension study in which all participants received the compound at the highest dose for 12 weeks. All doses were administered subcutaneously (under the skin) of the abdomen once a week.

All trial participants produced dystrophin, apparently in response to the treatment, at variable levels. After the 12-week extension phase of the trial, there was an average increase of 35.2 meters (about 115.5 feet) in the distance walked in six minutes compared to baseline measurements. No serious adverse events occurred, and no unwanted immune responses were detected.

Read the complete paper, which includes details of how each participant fared, without charge at Systemic administration of PRO051 in Duchenne muscular dystrophy.

Second phase 1 trial under way in Ohio

A second phase 1 study of PRO051/GSK2402968 (usually called GSK2402968) is under way and recruiting at Nationwide Children's Hospital in Columbus, Ohio. This study is for boys with DMD who are no longer walking and have certain dystrophin gene mutations. For details and contact information, see Assessing Safety and Tolerability of GSK2402968.

Editor's note 11/9/11: The second phase 1 trial of GSK2402968 has now completed enrollment.

Phase 2 and 3 studies of GSK2402968

Phase 2 and phase 3 studies of GSK2402968 in DMD are being conducted outside the United States. See Phase II Doubleblind Exploratory Study of GSK2401968 for the phase 2 study and A Clinical Study to Assess the Efficacy and Safety of GSK2402968 for the phase 3 study.

Screening under way for phase 1 study of AVI4658 in Ohio

Nationwide Children's Hospital in Columbus, Ohio, is pre-screening boys with DMD who have certain mutations in the dystrophin gene for an exon-skipping trial using a compound developed by AVI BioPharma called AVI4658. This compound is different from the Prosensa/GSK compound, but it targets the same part of the dystrophin gene.

The trial investigators are interested in pre-screening potential candidates with the following mutations in the gene: deletion of exons 45-50, 47-50, 48-50, 50, 52, or 52-63. Prospective trial participants who have these deletions will be tested by a physical therapist and will have the opportunity to ask questions about the trial, which is slated to start in late spring 2011.

Contact Ana Maria Gomez at Nationwide Children's at (614) 722-2715 or

Phase 1-2 trial of AVI4658 promising

In a recent trial of AVI4658 conducted in the United Kingdom, the compound was found to be well tolerated and to cause substantial dystrophin production in some participants without eliciting a harmful immune response. See Intravenous AVI4658 Shows Safety, Benefit in DMD.

Meaning for people with DMD

Exon-skipping compounds, while still experimental, are showing great promise for people with certain types of mutations in the dystrophin gene. They may be able to increase dystrophin levels enough to improve muscle function without eliciting an immune response, a problem that has occurred in gene therapy trials to transfer the dystrophin gene to muscle tissue.

Editor's note: This story was updated 11/9/11 to reflect the completion of enrollment for the phase 1 GSK2402968 trial in Ohio and France.

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