The families of children and young people with the severe genetic muscle-wasting condition Duchenne muscular dystrophy (DMD) received a heavy blow last week. The Dutch biotech Prosensa and GlaxoSmithKline announced the preliminary results of a phase III clinical trial. This study failed to demonstrate that the drug drisapersen could slow declining walking ability in children affected by the condition (see BioNews 723).
The trial was one of several testing the effectiveness of a technology called 'exon skipping'. While the full trial data will not be announced until later this year, this initial announcement has precipitated confusion and concern about exon skipping's future. Yet, when seen in context, the failure of this trial is certainly not the end for this pioneering technology.
There are great hopes that exon skipping could be able to reduce the severity of the symptoms in DMD, a condition which affects 2,000 people in the UK - almost all of them men and boys. While there are some means for managing symptoms, the use of steroids to reduce muscle inflammation in children for example, there are currently no treatments addressing the underlying genetic cause of the condition. Many of those born with DMD are unable to walk by the age of twelve and experience life-threatening cardiac and respiratory complications in their late teens. Few live to see their 30th birthday.
The Muscular Dystrophy Campaign spearheaded the development of exon skipping technology as a potential treatment for DMD from the early 1990s. The condition is caused by mutation in the dystrophin gene which leads to a lack of dystrophin protein in the muscles, causing them to weaken and waste over time.
The dystrophin gene contains 79 exons which must each fit together coherently with their neighbours so that the DNA message that they carry can be read and the protein that they are responsible for produced. If one or more of these exons are missing, the message in the remaining exons cannot be read, preventing the dystrophin protein being produced.
Exon skipping technology uses small pieces of DNA called antisense oligonucleotides, or 'molecular patches', to mask the exon next to the missing part of the gene. This helps the cell's biological machinery to ignore, or skip, that exon so that the rest of the message can be read. Cells can then produce a smaller dystrophin protein which retains some functionality. Whilst this would not cure the condition, it could reduce the severity of the symptoms of DMD to those seen in the milder Becker muscular dystrophy - potentially slowing muscle wastage, keeping children on their feet for longer, and impacting on length and quality of life.
Exon skipping is a highly personalised medicine - each exon will require a unique molecular patch that would only be able to treat certain specific mutations. The Prosensa and GlaxoSmithKline trial results are only directly applicable to drisapersen, designed specifically for exon 51. The failure of drisapersen in this trial does not necessarily mean that exon 51 cannot be skipped. In the USA, Sarepta Therapeutics is also testing a molecular patch for exon 51, based on a different chemistry (modifications to the molecular patch which may protect it in the body and help it to enter the muscles) to drisapersen. Just last week, interim results of this ongoing trial were released and were encouraging, although admittedly were based on only a small group of children.
The failure of this trial is a reminder that we should not focus or rely on any single avenue to reach an effective treatment. To do so would be putting all our eggs in a basket of unknown strength. Senior researchers in the neuromuscular field have suggested that a combination of treatments may be beneficial - or even necessary - to successfully treat boys with DMD. With the backing of our supporters, we at the Muscular Dystrophy Campaign will continue to fund a broad range of research projects investigating a range of technologies and techniques, including exon skipping, until effective treatments are available for every single child affected.
We are now looking ahead to the publication of a full analysis of the trial data later this year, to better understand what these results mean for the future of exon skipping.