Progress in Exon Skipping for DMD

Investigators presented intriguing data from a trial of an experimental exon skipping drug for Duchenne muscular dystrophy, at the 2010 American Academy of Neurology meeting

Article Highlights:
  • Skipping of exon (gene region) 51 by the experimental drug PRO051/GSK2402968 shows promise for people with Duchenne MD who have specific dystrophin gene mutations.
  • Eleven of 12 trial participants showed production of the needed dystrophin protein after they received the drug, and there were no serious adverse events.
  • Exon skipping is a strategy in which molecules called antisense oligonucleotides target error-containing parts of a gene and coax cells to retain the error-free parts for protein synthesis.
  • GlaxoSmithKline and Prosensa are collaborating on exon skipping for DMD. Prosensa has opened a new trial of PRO044, to target exon 44 of the dystrophin gene.
  • MDA continues to fund basic science research on exon skipping for DMD.
by Margaret Wahl on April 14, 2010 - 3:21am

The multinational pharmaceutical company GlaxoSmithKline (GSK) and the Dutch biotechnology company Prosensa  announced "intriguing results" following a 12-person trial of an experimental "exon skipping" therapeutic for Duchenne muscular dystrophy (DMD).

The investigators, who presented their findings Wednesday, April 14, 2010, at the annual meeting of the American Academy of Neurology (AAN) in Toronto, said the experimental construct, dubbed PRO051/GSK240968 (formerly called PRO051), appears to have resulted in production of dystrophin (the protein missing in DMD) and was, in general, well tolerated by trial participants.

About PRO051/GSK2402968

PRO051/GSK2402968 is an "exon skipping" molecule of a type known as an "antisense oligonucleotide." It's a construct designed to cause cells to "skip" (ignore) error-containing genetic instructions so that a functional protein can be made from the remaining, error-free instructions.

The absence or near-absence of the muscle protein dystrophin, caused by any of a large number of mutations in the X-chromosome dystrophin gene, is the underlying cause of DMD.

Laboratory experiments and preliminary results from human tests show it may be possible to offset the effects of some dystrophin mutations by causing muscle cells to skip specific exons in the dystrophin gene.

About the new PRO051/GSK2402968 findings

All muscle fibers analyzed from biopsy samples, with the exception of one in a patient who received the lowest dose of the experimental drug, showed clear dystrophin production. In general, the higher the dose, the more dystrophin was produced.

On the six-minute walk test, which measures the distance a patient can walk in six minutes, there was no significant change after five weeks. At 12 weeks, an increase in walking distance was seen in most trial participants, but the researchers cautioned that this was a small study, and they can't yet state firm conclusions about improvements in walking at this time.

The drug was well tolerated, with no serious adverse events.Local reactions at the injection site were seen. Some trial participants began excreting protein in their urine, which the investigators said is abnormal and needs to receive further followup.

'Proof of concept' in 2008

In December 2008, researchers at Prosensa announced they had achieved "proof of concept" for what was then called PRO051 in four boys with DMD. (See Trial Results in DMD Heralded as 'Proof of Concept.')

In this small pilot study, conducted in the Netherlands, all four participants had dystrophin gene mutations that the researchers predicted could be offset by bypassing exon 51.

Each boy received four injections of PRO051 in a lower leg muscle. A muscle biopsy a month later showed dystrophin production that was between 3 percent and 12 percent of a normal level of the protein. No functional changes were seen, but none were expected from the low dose and restricted area of injection in this initial study.

GSK and Prosensa working together

In October 2009, GlaxoSmithKline announced it would team up with Prosensa to develop exon skipping for DMD, starting with the Prosensa drug PRO051. (See Major Phamaceutical Company Commits to Develop Exon Skipping Drug.)

Exon 44 is next target

On March 30, Prosensa announced the start of a trial of PRO044, for which the target is skipping of exon 44 of the dystrophin gene, in boys with DMD in Europe who meet study criteria, including having mutations that have the potential to benefit from skipping of exon 44. (See Phase I/II Study of PRO044 in Duchenne Muscular Dystrophy (DMD).)

GSK has an option to collaborate with Prosensa on development of PRO044, which will be triggered upon successful completion of the phase 1-2 study of this construct.

MDA's role

MDA supported Judith van Deutekom, formerly at Leiden University in the Netherlands and now vice president for drug discovery at Prosensa, for development of exon skipping for DMD.

MDA also has supported and continues to support Steve Wilton at the University of Western Australia for exon skipping development for this disease.

Meaning for families with DMD

Exon skipping continues to show promise as a strategy for DMD. The involvement of a small biotechnology company and a major pharmaceutical company, as well as support from MDA for basic scientific research, bode well for further development of this approach.

However, many hurdles remain. Among them are the uncertainty of being able to deliver an exon skipping drug to muscle fibers in an efficient and safe manner; the ability to achieve and sustain sufficient levels of dystrophin production to make a functional difference in people with DMD; and the necessity to develop several different exon skipping constructs to target different parts of the very large dystrophin gene.

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