2. Academic Validation
  3. The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy

The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy

  • Acta Neuropathol Commun. 2021 Jan 6;9(1):7. doi: 10.1186/s40478-020-01106-1.
Dominic Scaglioni 1 2,  Francesco Catapano 1 2 3,  Matthew Ellis 4 5,  Silvia Torelli 1 2,  Darren Chambers 3,  Lucy Feng 3,  Matthew Beck 1 2,  Caroline Sewry 3 6,  Mauro Monforte 7,  Shawn Harriman 8,  Erica Koenig 8,  Jyoti Malhotra 8,  Linda Popplewell 9,  Michela Guglieri 10,  Volker Straub 10,  Eugenio Mercuri 7,  Laurent Servais 11 12,  Rahul Phadke 3,  Jennifer Morgan 1 2,  Francesco Muntoni 13 14
Affiliations

Affiliations

  • 1 Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, 30 Guilford St, London, WC1N 1EH, UK.
  • 2 NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
  • 3 Dubowitz Neuromuscular Centre, UCL Queen Square Institute of Neurology and Great Ormond Street, London, UK.
  • 4 Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK.
  • 5 School of Cancer Sciences, University of Southampton, Southampton, UK.
  • 6 RJAH Orthopaedic Hospital NHS Trust, Oswestry, UK.
  • 7 Paediatric Neurology and Centro Clinico Nemo, Catholic University and Policlinico Gemelli, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome, Italy.
  • 8 Sarepta Therapeutics, Inc., Cambridge, MA, USA.
  • 9 Centre of Gene and Cell Therapy and Centre for Biomedical Sciences, Royal Holloway, University of London, Egham, UK.
  • 10 Newcastle University John Walton Muscular Dystrophy Research Centre and the Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
  • 11 Institute I-Motion, Hôpital Armand-Trousseau, Paris, France.
  • 12 Neuromuscular Reference Centre, CHU Liège, Liège, Belgium.
  • 13 Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, 30 Guilford St, London, WC1N 1EH, UK. f.muntoni@ucl.ac.uk.
  • 14 NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. f.muntoni@ucl.ac.uk.
PMID: 33407808 DOI: 10.1186/s40478-020-01106-1
Abstract

During the last decade, multiple clinical trials for Duchenne muscular dystrophy (DMD) have focused on the induction of dystrophin expression using different strategies. Many of these trials have reported a clear increase in dystrophin protein following treatment. However, the low levels of the induced dystrophin protein have raised questions on its functionality. In our present study, using an unbiased, high-throughput digital image analysis platform, we assessed markers of regeneration and levels of dystrophin associated protein via immunofluorescent analysis of whole muscle sections in 25 DMD boys who received 48-weeks treatment with exon 53 skipping morpholino antisense oligonucleotide (PMO) golodirsen. We demonstrate that the de novo dystrophin induced by exon skipping with PMO golodirsen is capable of conferring a histological benefit in treated patients with an increase in dystrophin associated proteins at the dystrophin positive regions of the sarcolemma in post-treatment biopsies. Although 48 weeks treatment with golodirsen did not result in a significant change in the levels of fetal/developmental myosins for the entire cohort, there was a significant negative correlation between the amount of dystrophin and levels of regeneration observed in different biopsy samples. Our results provide, for the first time, evidence of functionality of induced dystrophin following successful therapeutic intervention in the human.

Keywords

Clinical trial; Dystrophin; Genetic therapies; Golodirsen; Immunofluorescence; Muscular dystrophy.

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