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Every year in the EU, around 800 boys are born with Duchenne muscular dystrophy (DMD) caused by mutations in the dystrophin gene. Without the dystrophin protein, muscle cells eventually die. Children with DMD are paralysed by their teenage years and rarely live beyond their twenties.
As part of the search for a safe, effective treatment, the EU-funded SKIP-NMD project developed a new medicine using an approach called exon skipping, in partnership with the drug company Sarepta Therapeutics.
This method encourages the body’s cellular machinery to skip the part of the gene (the exon) that is mutated. As a result, muscle cells are able to produce a shortened but functional version of dystrophin. Exon skipping treatment cannot cure the disease entirely, but could slow down disease progression – delaying both the loss of a patient’s ability to walk and his or her need for breathing assistance.
SKIP-NMD researchers focused their efforts on developing a therapy for the 8 % of children with DMD who have mutations in exon 53 of the dystrophin gene. A medicine called golodirsen was developed during the project, which ended in April 2016. Golodirsen has since received conditional approval for use in the United States and Sarepta Therapeutics is currently conducting further clinical trials.
‘Our original study produced the highest level of evidence that golodirsen is safe. This was extremely reassuring and cannot be said of all drugs developed for Duchenne,’ says Francesco Muntoni of the UCL Great Ormond Street Institute of Child Health, and NIHR Biomedical Research Centre at Great Ormond Street Hospital in the UK.
‘The clinical benefits are being measured in our study and in the larger ESSENCE study being run by Sarepta, with results scheduled to be released in 2020. We expect that treated children will have a slower disease progression, including a slower decline in respiratory function.’
Clinical trials with children
The project’s first challenge was to find a lead molecule that would bind to exon 53. Researchers tested a large number of different compounds in cells that had been taken from children suffering from DMD.
They went on to demonstrate the safety of golodirsen, administering it to children by means of weekly intravenous injections over many months to allow dystrophin to build up in the muscles.
The same trial also looked at the drug’s ability to induce the skipping of exon 53. After 48 weeks, SKIP-NMD researchers searched for dystrophin in biopsies taken from the treated children’s muscles. They also studied the health of the muscle using magnetic resonance imaging and magnetic resonance spectroscopy. The project developed a novel, high-throughput method to work out how much dystrophin was produced.
Longer-term assessments looked at whether the drug was capable of slowing down disease progression. As well as using traditional outcome measures, one of the companies associated with SKIP-NMD, Sysnav, developed new data-tracking devices. Thus, for the first time, the project was able to assess muscle preservation using muscle magnetic resonance imaging, and the speed and distance covered by patients each day using the tracking device. These devices are now being used in many international clinical trials.
Future medicines
‘Now that our approach has demonstrated the proof of concept, other exons are being targeted – for example, exon 45, in another trial by Sarepta,’ adds Muntoni. ‘And work is already going into a second-generation drug, to continue to improve the efficiency of these medicinal products in the future.’
Muntoni is now project coordinator for the EU-funded Horizon 2020 BIND project which aims to understand the role played by dystrophin produced in the brain in DMD and in Becker muscular dystrophy.