Exon skipping is an experimental therapeutic strategy in which regions — exons— of a gene are targeted and blocked ("skipped") by laboratory-designed molecules. The goal is that the remaining genetic instructions will lead to production of a shorter but still-functional protein.
Exon skipping for Duchenne muscular dystrophy (DMD) targets the dystrophin gene with the aim of producing functional dystrophin protein in muscle fibers.
A phase 3 clinical trial of the experimental exon-skipping drug GSK2402968, conducted at 45 non-U.S. locations throughout the world, has completed enrolling participants, says its developer, GlaxoSmithKline, in an Aug. 10, 2012, email communication. The communication also said the study is expected to be completed in July 2013 and that results are expected in late 2013.
The drug targets exon 51 of the dystrophin gene and is designed to treat DMD caused by specific mutations.
For details, see A Clinical Study to Assess the Efficacy and Safety of GSK2402968 in Subjects with Duchenne Muscular Dystrophy; or enter NCT01254019 in the search box at ClinicalTrials.gov.
In addition, GSK says it will now call GSK2402968 by the generic name drisapersen. A phase 2 trial is open in the United States. For details on the U.S. study, see A Clinical Study to Assess Two Doses of GSK2402968 in Subjects with Duchenne Muscular Dystrophy; or enter study number NCT01462292 in the search box at ClinicalTrials.gov.
Skipping a relatively large but possibly nonessential part of the instructions for the dystrophin gene in a mouse model of DMD appears to be a promising therapeutic lead.
People missing exons 45-55 of the dystrophin gene generally have very mild symptoms, leading researchers to conclude that the dystrophin protein they make, even though it's missing a rather large section, remains functional. (The mice used in these experiments lacked exon 52; the more commonly used DMD mouse model has a mutation in exon 23.)
Yoshitsugu Aoki at the National Institute of Neuroscience in Tokyo, and colleagues, found that systemic injections of 10 different exon-skipping compounds, targeting exons 45-55 of the dystrophin gene, led to production of up to 15 percent of the normal level of dystrophin protein in skeletal muscles.
The dystrophin was apparently functional, even though it was considerably shorter than normal. It localized to the right place at the muscle-fiber membrane, increased strength in the animals, and improved the appearance of the muscle tissue, all without any detectable toxicity.
The investigators say their "block-skipping" approach, if confirmed to be safe and effective, has the potential to help a far greater percentage of people with DMD than current exon skipping compounds now in clinical trials, which target only exon 51. It's been estimated that about 10 percent of the DMD population could potentially be treated by skipping this particular exon.
Several of the investigators on this study have received MDA funding, although not for this particular project.