The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy
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...
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doaj-0bb99a8919a34521a7b32c5a0a2450872021-01-10T12:44:11ZengBMCActa Neuropathologica Communications2051-59602021-01-019111710.1186/s40478-020-01106-1The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophyDominic Scaglioni0Francesco Catapano1Matthew Ellis2Silvia Torelli3Darren Chambers4Lucy Feng5Matthew Beck6Caroline Sewry7Mauro Monforte8Shawn Harriman9Erica Koenig10Jyoti Malhotra11Linda Popplewell12Michela Guglieri13Volker Straub14Eugenio Mercuri15Laurent Servais16Rahul Phadke17Jennifer Morgan18Francesco Muntoni19Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child HealthDubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child HealthDepartment of Neurodegenerative Diseases, UCL Queen Square Institute of NeurologyDubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child HealthDubowitz Neuromuscular Centre, UCL Queen Square Institute of Neurology and Great Ormond StreetDubowitz Neuromuscular Centre, UCL Queen Square Institute of Neurology and Great Ormond StreetDubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child HealthDubowitz Neuromuscular Centre, UCL Queen Square Institute of Neurology and Great Ormond StreetPaediatric Neurology and Centro Clinico Nemo, Catholic University and Policlinico Gemelli, Fondazione Policlinico Universitario Agostino Gemelli IRCSSSarepta Therapeutics, Inc.Sarepta Therapeutics, Inc.Sarepta Therapeutics, Inc.Centre of Gene and Cell Therapy and Centre for Biomedical Sciences, Royal Holloway, University of LondonNewcastle University John Walton Muscular Dystrophy Research Centre and the Newcastle Hospitals NHS Foundation TrustNewcastle University John Walton Muscular Dystrophy Research Centre and the Newcastle Hospitals NHS Foundation TrustPaediatric Neurology and Centro Clinico Nemo, Catholic University and Policlinico Gemelli, Fondazione Policlinico Universitario Agostino Gemelli IRCSSInstitute I-Motion, Hôpital Armand-TrousseauDubowitz Neuromuscular Centre, UCL Queen Square Institute of Neurology and Great Ormond StreetDubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child HealthDubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child HealthAbstract 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.https://doi.org/10.1186/s40478-020-01106-1DystrophinMuscular dystrophyImmunofluorescenceGenetic therapiesGolodirsenClinical trial |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Dominic Scaglioni Francesco Catapano Matthew Ellis Silvia Torelli Darren Chambers Lucy Feng Matthew Beck Caroline Sewry Mauro Monforte Shawn Harriman Erica Koenig Jyoti Malhotra Linda Popplewell Michela Guglieri Volker Straub Eugenio Mercuri Laurent Servais Rahul Phadke Jennifer Morgan Francesco Muntoni |
spellingShingle |
Dominic Scaglioni Francesco Catapano Matthew Ellis Silvia Torelli Darren Chambers Lucy Feng Matthew Beck Caroline Sewry Mauro Monforte Shawn Harriman Erica Koenig Jyoti Malhotra Linda Popplewell Michela Guglieri Volker Straub Eugenio Mercuri Laurent Servais Rahul Phadke Jennifer Morgan Francesco Muntoni The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy Acta Neuropathologica Communications Dystrophin Muscular dystrophy Immunofluorescence Genetic therapies Golodirsen Clinical trial |
author_facet |
Dominic Scaglioni Francesco Catapano Matthew Ellis Silvia Torelli Darren Chambers Lucy Feng Matthew Beck Caroline Sewry Mauro Monforte Shawn Harriman Erica Koenig Jyoti Malhotra Linda Popplewell Michela Guglieri Volker Straub Eugenio Mercuri Laurent Servais Rahul Phadke Jennifer Morgan Francesco Muntoni |
author_sort |
Dominic Scaglioni |
title |
The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy |
title_short |
The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy |
title_full |
The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy |
title_fullStr |
The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy |
title_full_unstemmed |
The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy |
title_sort |
administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with duchenne muscular dystrophy |
publisher |
BMC |
series |
Acta Neuropathologica Communications |
issn |
2051-5960 |
publishDate |
2021-01-01 |
description |
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. |
topic |
Dystrophin Muscular dystrophy Immunofluorescence Genetic therapies Golodirsen Clinical trial |
url |
https://doi.org/10.1186/s40478-020-01106-1 |
work_keys_str_mv |
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