GOSH research brings Duchenne muscular dystrophy drug one step closer to UK patients


A drug that ‘skips over’ a genetic fault responsible for the fatal muscle-wasting condition Duchenne muscular dystrophy (DMD) has shown promising results in an international trial led by Great Ormond Street Hospital (GOSH).

All 25 children and young people treated with golodirsen showed a significant increase in levels of dystrophin, a vital muscle-protecting protein that DMD patients cannot normally produce. Without dystrophin, affected children experience progressive muscle loss, with most needing a wheelchair by their teens and passing away by their early thirties.

Published today in the online issue of Neurology®, the medical journal of the American Academy of Neurology, the study suggests a DNA-skipping approach can lead to the production of crucial dystrophin, which is expected to slow progression of the disease. The results also indicate that golodirsen is safe and well tolerated by young patients. This new, personalised approach is suitable for around 8% of affected children.

“The success of this study is a significant step towards an effective treatment for children with DMD,” says Professor Francesco Muntoni, lead researcher and GOSH Paediatric Neurologist. “Golodirsen appears to restore dystrophin production in patients with a particular type of genetic mistake, to levels that we think could noticeably slow muscle damage. We must now gather more evidence, but these findings will bolster the application for the drug’s approval in Europe when the time comes.”

DMD is the most common and lethal form of muscle-wasting disease affecting boys in the UK. Around 100 boys are born with the condition each year.

Golodirsen is designed to ‘skip over’ a particular type of genetic fault that causes DMD, by removing a small section of DNA known as exon 53. Faults of this type are responsible for 8% - approximately 200 - of an estimated 2,500 cases in the UK.

Genetic DMD treatments are complicated by the sheer size of the affected gene. “The dystrophin gene is so large that it takes our cells around 16 hours to make a single copy,” says Professor Muntoni. “I ask families to imagine the Golden Gate Bridge, which is 3km long and very robust. But if you cut out a tiny section in the middle, the bridge would collapse. The dystrophin gene is the same – it’s a huge stretch of DNA and most children with DMD only have a tiny section missing, but that means they can’t produce any dystrophin.

“What we’re trying to do with exon skipping is to rest a plank across the gap. It’s not as good as restoring the original bridge, but it’s enough to re-establish the connection between the two parts of the gene and allow production of some dystrophin.”

The ‘plank’ – known as an antisense oligonucleotide – allows the body to read past the error and produce a shortened version of the protein.

Golodirsen was developed and trialed by an EU-funded consortium known as SKIP-NMD, led by Professor Muntoni and comprising four centres from the UK and Europe. Patients on the trial, aged 6-15 years were recruited by centres in London, Newcastle, Paris and Rome, including eight children treated in the GOSH NIHR Clinical Research Facility.

Based on the study’s findings and an urgent need for effective treatments, the US Food and Drug Administration (FDA) granted accelerated approval of golodirsen in late 2019. Professor Muntoni expects the European Medicines Agency (EMA) approval process to follow, once a longer, parallel trial of the drug for DMD is completed next year.

“EMA approval will require evidence of clinical benefit – a reduction in muscle loss and slowed disease progression. We’re gathering further data through a parallel two-year study funded by Sarepta Therapeutics, with whom we collaborated during the SKIP NMD trial. This study, called ‘ESSENCE’, is designed to confirm whether golodirsen slows muscle wasting and slows the decline in mobility.

“I hope within a few years that there will be the evidence needed to apply for EMA approval. There are other hurdles after that to expand access for UK patients, but we’re in a very good position to move forward with such positive results from this trial.”

UK patients on the trial will continue to have access to the drug, which is given via a weekly injection. Others are receiving the treatment through the parallel ESSENCE trial.

The golodirsen study was funded by the European Union (SKIP-NMD Grant Proposal 305370-2, FP7-Health-2012-Innovation-1) and by Sarepta Therapeutics. This research also received support from the National Institute of Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre (BRC), GOSH Charity, patient advocacy groups, the MRC Centre for Neuromuscular Diseases, the DMD-HUB and Muscular Dystrophy UK.

About Great Ormond Street Hospital for Children NHS Foundation Trust 

Founded in 1852, Great Ormond Street Hospital is one of the world’s leading children’s hospitals with the broadest range of dedicated, children’s healthcare specialists under one roof in the UK. With more than 252,000 outpatient and 43,000 inpatient visits every year, the hospital’s pioneering research and treatment gives hope to children from across the UK with the rarest, most complex and often life-threatening conditions. As an international centre of excellence in child healthcare, our patients and families are central to everything we do – from the moment they come through the door and for as long as they need us. Visit www.gosh.nhs.uk

Research at GOSH is underpinned by support from the National Institute of Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre (BRC) and GOSH Charity.

About the UCL Great Ormond Street Institute of Child Health (ICH) 

The UCL Great Ormond Street Institute of Child Health (ICH) is part of the Faculty of Population Health Sciences within the School of Life and Medical Sciences at University College London. Together with its clinical partner Great Ormond Street Hospital for Children NHS Foundation Trust (GOSH), it forms the UK's only paediatric National Institute for Health Research (NIHR) Biomedical Research Centre and has the largest concentration of children's health research in Europe. For more information visit www.ucl.ac.uk/child-health

About the NIHR

The National Institute for Health Research (NIHR) is the nation's largest funder of health and care research. The NIHR:

  • Funds, supports and delivers high quality research that benefits the NHS, public health and social care
  • Engages and involves patients, carers and the public in order to improve the reach, quality and impact of research
  • Attracts, trains and supports the best researchers to tackle the complex health and care challenges of the future
  • Invests in world-class infrastructure and a skilled delivery workforce to translate discoveries into improved treatments and services
  • Partners with other public funders, charities and industry to maximise the value of research to patients and the economy

The NIHR was established in 2006 to improve the health and wealth of the nation through research, and is funded by the Department of Health and Social Care. In addition to its national role, the NIHR supports applied health research for the direct and primary benefit of people in low- and middle-income countries, using UK aid from the UK government.

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