DMD: Exon-Skipping Timeline

by Amy Madsen on July 25, 2013 - 3:29am

Ever since the discovery in 1986 of the gene for dystrophin, the protein that’s missing or deficient in Duchenne muscular dystrophy (DMD), scientists and physicians have been trying to figure out how to compensate for its loss.

Exon skipping is a strategy currently being developed for DMD in which sections of genetic code called exons are “skipped,” allowing the creation of shortened but partially functional dystrophin. Exon skipping is not a cure for DMD, but it potentially could lessen the severe muscle weakness and atrophy that is the hallmark of this disease.

Laboratory development of exon skipping began in the 1990s with significant funding from MDA.

For more, see Exon Skipping in DMD: What Is It and Whom Can it Help?

Updated September 20, 2013


{ 1997 }

MDA funds
Stephen Wilton

Early results in mice


{ 2003 }


{ 2003-2006 }

MDA funds
Judith van Deutekom


Exon-skipping studies in
a cell model

Exon-skipping studies in
a mouse model

{ 2006 }  

{ 2007 }

Human clinical trial tests
safety, tolerability

First human clinical
trial results

AVI BioPharma launches
second clinical trial

Exon skipping successful
in dogs with DMD

GlaxoSmithKline commits to
developing PRO051

Other exons targeted

{ 2009 }

  { 2010 }

Dystrophin protein produced
in PRO051/GSK240968 trial

Dystrophin protein
produced in AVI4658 trial

First U.S. exon-skipping
trial opens

Sarepta Therapeutics reports
safety benefit from eteplirsen
in a 19-person trial

No unwanted immune response
seen in AVI4658/eteplirsen trial

Prosensa targets exons
45, 53, 52, and 55

Phase 2 trial of eteplirsen
opens in the U.S.
with MDA support

Sarepta Therapeutics and the
NIH target exons 45 and 50

{ 2011 }  
  { 2012 }

Sarepta Therapeutics reports
24-week results for eteplirsen

Sarepta Therapeutics reports
36-week results for eteplirsen

“Accelerated approval pathway”
for rare drugs approved,
with MDA support

"Open Letter" addresses
eteplirsen development

Phase 2 and 3 trials of

Prosensa targets exons
44, 45, 52, 53 and 55

Sarepta Therapeutics reports
48-week results for eteplirsen

GlaxoSmithKline reports
phase 1 trial results for drisapersen

Sarepta Therapeutics expands
its exon-skipping program for DMD

Orphan drug status assigned for
additional exon-skipping compounds

U.S. FDA talks with Sarepta
Therapeutics about eteplirsen

GlaxoSmithKline discusses
development of drisapersen

Drisapersen receives breakthrough
therapy designation

New drug application will be
filed for eteplirsen in 2014

Prosensa initiates trial of drug targeting exon 53

Drisapersen phase 3 results show no benefit

{ 2013 }


MDA begins funding Stephen Wilton at the University of Western Australia in Perth to develop a technique for blocking specific exons of genes, thereby restoring the reading frame so that shortened but functional proteins can be produced. Wilton, who continues to receive MDA support, has since worked with Sarepta Therapeutics (formerly AVI BioPharma) to continue development of the therapeutic strategy.

Stephen Wilton and colleagues demonstrate that treatment with a particular exon-skipping compound allows mdx mice to produce normal levels of dystrophin protein in a large number of muscle fibers.

MDA begins funding Judith van Deutekom at Leiden (Netherlands) University Medical Center to develop exon skipping related to the dystrophin gene. She later moves to Dutch biotechnology company, Prosensa, where she is now vice president of drug discovery and continues this work.

Graham McClorey and colleagues report online in Gene Therapy that they have achieved success in causing muscle cells taken from dogs with a disorder similar to human DMD to produce functional dystrophin. The exon-skipping treatment allows production of nearly full-length dystrophin, with no apparent adverse effects on the cells.

Abbie Fall and colleagues report in Genetic Vaccines and Therapy that they have successfully applied the exon-skipping strategy in DMD mice to a wider range of genetic mutations than had previously been targeted.

Sarepta Therapeutics (then AVI BioPharma) opens an exon-skipping trial in the United Kingdom to test a compound called AVI4658. The study is designed to assess safety and tolerability of AVI4658, which targets exon 51, as well as determine proper dosage of the compound when injected into a single muscle, in children with DMD.

Results from a clinical trial, conducted in the Netherlands, to test Prosensa’s experimental exon-skipping compound PRO051 in four boys with DMD show that smaller-than-normal, but potentially functional, dystrophin protein molecules were produced in all four participants. Similarly to AVI4658, PRO051 is designed to target exon 51. The trial results are considered "proof of concept," for exon skipping as a strategy to treat DMD.

After announcing that AVI4658 yielded promising results in its phase 1 clinical trial, Sarepta Therapeutics, initiates a second clinical trial, also in the United Kingdom, designed to test whether intravenous injection of AVI4658 can cause more widespread dystrophin protein production.

Scientists at Children's National Medical Center in Washington, D.C., Carolinas Medical Center in Charlotte, N.C., and the National Center of Neurology and Psychiatry in Tokyo, successfully treated dogs with a disease closely resembling DMD, using a molecular treatment strategy called "exon skipping." The investigators, who were partially supported by MDA, showed intravenous injections of a "cocktail" of laboratory-developed compounds coaxed the muscle fibers of three DMD-affected dogs to produce functional dystrophin protein.

GlaxoSmithKline, announces it will develop and commercialize the experimental exon-skipping compound PRO051 for DMD. The commitment of a major pharmaceutical company to development of a drug for DMD is welcome news for families with this disease.

Prosensa initiates a pilot study to test an exon-skipping compound called PRO044 in people with DMD. The compound is designed to target exon 44.

GlaxoSmithKline and Prosensa announce findings from a 12-person trial showing that PRO051/GSK240968 (formerly called PRO051) resulted in production of dystrophin and was, in general, well-tolerated by trial participants.

Earlier results from Sarepta Therapeutics indicated that AVI4658 had shown promising results when delivered intravenously to 19 trial participants. Further analysis in 2010 showed that some trial participants had greatly increased dystrophin protein production.

PRO051/GSK2402968 is the first exon-skipping drug to be tested in clinical trials in the United States. The trial opens at Nationwide Children’s Hospital in Columbus, Ohio, and is among the first to test participants with DMD who are nonambulatory.

Sarepta Therapeutics reports findings from its completed 19-person trial of eteplirsen (formerly called AVI4658) in DMD, showing that it was well-tolerated and resulted in increased production of the needed dystrophin protein without eliciting an unwanted immune response.

A phase 2 clinical trial of eteplirsen opened at Nationwide Children’s Hospital under the direction of Jerry R. Mendell, co-director of the MDA Clinic at Nationwide Children’s Hospital. MDA provided $110,000 in supplemental funding to help defray travel costs for families participating in the study, to support the processing and analysis of biopsy samples, and to fund the services of a clinical evaluator.

Prosensa works on the development of molecules designed to coax skipping of exons 45, 53, 52 and 55.

A phase 2 clinical trial of eteplirsen opened at Nationwide Children’s Hospital under the direction of Jerry R. Mendell, co-director of the Muscular Dystrophy Association Clinic at Nationwide Children’s. MDA provided $110,000 in supplemental funding to help defray travel costs for families participating in the study, to support the processing and analysis of biopsy samples, and to fund the services of a clinical evaluator.

Sarepta Therapeutics announces it will collaborate with Children’s National Medical Center in Washington, D.C., Carolinas Medical Center in Charlotte, N.C., and the U.S. National Institutes of Health (NIH) to develop two new exon-skipping compounds — one to encourage cells to skip exon 45, and the other to skip exon 50 of the dystrophin gene.

Sarepta Therapeutics reports that 24 weeks of treatment with eteplirsen resulted in significant increases in dystrophin production in the muscles of boys with DMD in its U.S. trial. Despite the increase in protein production, there were no significant improvements in clinical outcomes, such as distance walked in six minutes, compared to a placebo group.

Sarepta Therapeutics reports that 36 weeks of treatment with eteplirsen resulted in a significant clinical benefit on the six-minute walk test in its phase 2b trial in DMD.

Reauthorization of the Prescription Drug User Fee Act (PDUFA) was approved in July 2012. The legislation includes an “accelerated approval pathway” that speeds up the approval process for new drugs aimed at rare diseases, such as exon-skipping drugs for DMD. MDA urged Congress to include the “fast track” provision in the PDUFA bill, and MDA Advocates were part of the push to pass the new provision.

Sarepta Therapeutics issues an "open letter" explaining its development of eteplirsen for DMD. Toward the end of the year, it discusses possible FDA approval of eteplirsen and future trials.

Drisapersen (formerly known as PRO051/GSK2402968) is being tested in an ongoing phase 2 trial in the United States and in a phase 3 trial at 45 centers outside the United States, under the auspices of GlaxoSmithKline.

Prosensa begins developing compounds targeting dystrophin exons 44, 45, 52, 53 and 55. PRO044, targeting exon 44 of the dystrophin gene, is being tested in a clinical trial in Europe.

In October, Sarepta Therapeutics announces encouraging 48-week results for its 12-person, phase 2b trial of eteplirsen, and, later, promising results at 62 weeks. The six ambulatory trial participants who received eteplirsen for the entire 62 weeks walked farther than the four ambulatory participants who received a placebo for the first 24 weeks, followed by eteplirsen (placebo/delayed-treatment group).

GlaxoSmithKline announces promising results for its phase 1 trial of the exon-skipping drug drisapersen in boys with DMD who are no longer walking. Results showed that drisapersen (formerly GSK2402968) reached blood levels roughly proportional to the injected dose at two of the three dosage levels tested and that adverse events were not serious.

Sarepta Therapeutics plans to target additional dystrophin exons 45, 50 and 53 as potential DMD treatments. Targeting exon 53 addresses one of the most prevalent sets of mutations in DMD that’s amenable to treatment via exon skipping.

Prosensa receives orphan drug status in the United States for exon-skipping compounds in development for the treatment of muscular dystrophy, including PRO045, PRO052, PRO053 and PRO055.

The U.S. Food and Drug Administration (FDA) has said it will consider accepting an application from Sarepta Therapeutics for accelerated approval for eteplirsen after it reviews additional data from clinical trials of the drug. A phase 3 confirmatory trial for the drug is slated for early 2014.

GlaxoSmithKline has indicated that the earliest the company would file an application for approval of drisapersen in the United States or Europe would be the first quarter of 2014.

Sarepta Therapeutics announced in a July 24, 2013, press release that the company will submit a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) in the first half of 2014, based on a July 23 meeting the company had with the agency. Sarepta does not yet know whether eteplirsen will be eligible for the FDA’s accelerated approval program.

PRO053, Prosensa’s fourth drug development candidate, induces exon 53 skipping and may be applicable to approximately 8 percent of all DMD patients. PRO053 is being tested in an open-label study designed to assess the safety, efficacy, tolerability and pharmacokinetics of multiple doses of the compound in a subset of patients with DMD. The initial dose-finding portion of the study will be conducted at several clinical trial sites in Europe. The study may then be extended to additional territories in and outside of Europe.

A large-scale, phase 3 trial of drisapersen found no statistically significant differences on tests of walking distance or motor function between trial participants treated with the drug and those treated with a placebo. The results were jointly announced in a Sept. 20, 2013, press release from drisapersen’s developers, GlaxoSmithKline and Prosensa.

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