Families around the world afflicted by Duchenne muscular dystrophy await the results, due later this year, from a phase III trial of the compound drisapersen. Results from earlier, smaller studies are encouraging, suggesting improvement in walking ability after only 12 weeks of treatment.
But the therapy, which relies on an approach called 'exon skipping', might never have made it further than the lab bench without the financial support of muscular dystrophy patient groups and charities.
Dr Annemieke Aartsma-Rus, associate professor at the Department of Human Genetics of the Leiden University Medical Centre - who has been involved in developing exon-skipping treatments since starting her PhD in 2000 - says: 'When we started out developing this, the approach was almost frowned upon. People really didn't think it would work. Ultimately it was a patient organisation, the Dutch Duchenne Parent Project, that believed in us and provided essential early funding. They were then joined by other patient organisations and other forms of national and international funding.'
Duchenne muscular dystrophy is a progressive, muscle-wasting disease and most patients require a wheelchair by the age of 12. Average life expectancy is 27. The disease is caused by a fault in the gene DMD, which codes for the protein dystrophin.
The sections of genes that actually code for proteins are called exons (while the so-called 'junk DNA' sections are known as introns). Duchenne muscular dystrophy normally occurs when one of these exons has been deleted.
However, it's not deletion of the exon which the problem, so much as the fact that such deletion will make the gene unreadable. The result is a completely non-functional protein.
Exon skipping introduces a 'molecular patch' over an exon to make the gene readable again, allowing the production of a shorter from of dystrophin, but one which is far more functional than the untreated version.
Drisapersen, which was exclusively licensed to GlaxoSmithKline by Prosensa in 2009, patches exon 51. It is a potential therapy for the 13% of all Duchenne patients with an amenable mutation.
Now, new results from mouse studies are supplementing information from clinical trials to bolster confidence in the approach.
'My group has been studying how long the compound and its effect last in different tissues', says Dr Aartsma-Rus. 'What we find is that the compound and the exon-skipping effect disappear relatively quickly but the protein stays around much longer, so the protein is quite stable.'
Another unexpected finding from the mouse studies relates to how much dystrophin might be required to stem the decline in symptoms. Researchers have long used the figure of 20% of normal levels, based on a publication from several years back.
Dr Aartsma-Rus' recent experiments suggest that this figure may need to be revised: 'We used a severe mouse model that normally has a lifespan of about 12 weeks. What our research shows is that even animals with less than 3% of normal dystrophin have significantly improved survival. If you want to completely correct the disease in the mouse you need more than this, but even so, a little dystrophin does seem to go a long way.'
All eyes are on drisapersen's phase III clinical trial now, says Dr Aartsma-Rus, with results due later this year.
'What I hope - what we all hope - is that exon-skipping will indeed turn out to be a way to slow down disease progression in Duchenne patients. If it does work out, it would be largely thanks to the patient groups who supported us early on.'