[en] Duchenne muscular dystrophy (DMD) is caused by the lack of dystrophin, but many patients have rare revertant fibers that express dystrophin. The skeletal muscle pathology of DMD patients includes immune cell infiltration and inflammatory cascades. There are several strategies to restore dystrophin in skeletal muscles of patients, including exon skipping and gene therapy. There is some evidence that dystrophin restoration leads to a reduction in immune cells, but dystrophin epitopes expressed in revertant fibers or following genome editing, cell therapy, or microdystrophin delivery after adeno-associated viral gene therapy may elicit T cell production in patients. This may affect the efficacy of the therapeutic intervention, and potentially lead to serious adverse events. To confirm and extend previous studies, we performed annual enzyme- linked immunospot interferon-gamma assays on peripheral blood mononuclear cells from 77 pediatric boys with DMD recruited into a natural history study, 69 of whom (89.6%) were treated with corticosteroids. T cell responses to dystrophin were quantified using a total of 368 peptides spanning the entire dystrophin protein, organized into nine peptide pools. Peptide mapping pools were used to further localize the immune response in one positive patient. Six (7.8%) patients had a T cell-mediated immune response to dystrophin at at least one time point. All patients who had a positive result had been treated with corticosteroids, either prednisolone or prednisone. Our results show that ∼8% of DMD individuals in our cohort have a pre-existing T cell-mediated immune response to dystrophin, despite steroid treatment. Although these responses are relatively low level, this information should be considered a useful immunological baseline before undertaking clinical trials and future DMD studies. We further highlight the importance for a robust, reproducible standard operating procedure for collecting, storing, and shipping samples from multiple centers to minimize the number of inconclusive data.
Disciplines :
Pediatrics
Author, co-author :
Anthony, Karen; The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom ; National Institute for Health Research, Great Ormond Street Institute of Child Health Biomedical Research Centre, University College London, London, United Kingdom ; Centre for Physical Activity and Life Sciences, University of Northampton, Northampton, United Kingdom
Ala, Pierpaolo; The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom ; National Institute for Health Research, Great Ormond Street Institute of Child Health Biomedical Research Centre, University College London, London, United Kingdom
Catapano, Francesco; The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom ; National Institute for Health Research, Great Ormond Street Institute of Child Health Biomedical Research Centre, University College London, London, United Kingdom
Meng, Jinhong; The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom ; National Institute for Health Research, Great Ormond Street Institute of Child Health Biomedical Research Centre, University College London, London, United Kingdom
Domingos, Joana; The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom ; National Institute for Health Research, Great Ormond Street Institute of Child Health Biomedical Research Centre, University College London, London, United Kingdom
Perry, Mark; The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom ; National Institute for Health Research, Great Ormond Street Institute of Child Health Biomedical Research Centre, University College London, London, United Kingdom
Ricotti, Valeria; The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom ; National Institute for Health Research, Great Ormond Street Institute of Child Health Biomedical Research Centre, University College London, London, United Kingdom
Maresh, Kate; The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom ; National Institute for Health Research, Great Ormond Street Institute of Child Health Biomedical Research Centre, University College London, London, United Kingdom
Phillips, Lauren C; John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom ; Department of Pharmacology, University of Oxford, Oxford, United Kingdom
Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques ; Institut de Myologie, Groupe hospitalier La Pitié Salpétrière, Paris, France ; MDUK Oxford Neuromuscular Center, University of Oxford, Oxford, United Kingdom
Seferian, Andreea M; I-Motion, Hopital Trousseau, Paris, France
De Lucia, Silvana; I-Motion, Hopital Trousseau, Paris, France
de Groot, Imelda; Radboud University Medical Centre, Nijmegen, Netherlands
Krom, Yvonne D; Leiden University Medical Centre, Leiden, Netherlands
Verschuuren, J G M; Leiden University Medical Centre, Leiden, Netherlands
Niks, Erik H; Leiden University Medical Centre, Leiden, Netherlands
Straub, Volker; John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
Guglieri, Michela; John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
Voit, Thomas; National Institute for Health Research, Great Ormond Street Institute of Child Health Biomedical Research Centre, University College London, London, United Kingdom
Morgan, Jennifer ; The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom ; National Institute for Health Research, Great Ormond Street Institute of Child Health Biomedical Research Centre, University College London, London, United Kingdom
Muntoni, Francesco; The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, United Kingdom ; National Institute for Health Research, Great Ormond Street Institute of Child Health Biomedical Research Centre, University College London, London, United Kingdom
We acknowledge Dr. Katie Campbell, Prof. Kevin Flanigan, Prof. Christopher Walker, and Prof. Jerry Mendell for sharing their ELISPOT expertise. We would like to thank Dr. Valentina Sardone for her help in preparing cells and Dr. Petra Disterer for her assistance. We thank Georgia Stimpson for statistical advice. The support of the MRC Centre for Neuromuscular Diseases Biobank is gratefully acknowledged. Je.M. was supported by Great Ormond Street Hospital Children's Charity. This research was supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.V.S. is or has been on advisory boards for Astellas Gene Therapies, Biogen, Edgewise Therapeutics, Kate Therapeutics, ML Bio Solutions, Novartis Gene Therapies, Roche, Sanofi Genzyme, Sarepta Therapeutics, Vertex Pharmaceuticals, and Wave Therapeutics. He received speaker honoraria from Sanofi Genzyme and Sarepta Therapeutics and has research collaborations with the two companies. M.G. is Study Chair for VBP15-004 study sponsored by ReveraGen, Chief Medical Coordinator for DMD study funded by NIH, Chief Investigator/Principal Investigator for clinical trials of Pfizer, Italfarmaco, Santhera, Roche, ReveraGen, Dynacure, and Edgewise. M.G. is a member of Advisory boards for Pfizer, NS Pharma, and Dyne (honoraria through Newcastle University), and has been given speaker honoraria from Sarepta and Novartis (2019, 2021, 2022).L.S. reports consultancy for Pfizer, Sarepta, Santhera, Biophytis, and Regenx Bio., and is on the data and safety monitoring board of Fibrogen. I.d.G. was in the past principal investigator of several drug trials (Italfarmaco, NSPharma, and ReveraGen). E.H.N. report grants from Spieren voor Spieren, Duchenne Parent Project, ZonMW, AFM, and PPMD. He has been site principal investigator for clinical trials conducted by BioMarin, GSK, Eli Lilly, Santhera Pharmaceuticals, Italfarmaco SpA, Roche Pharma, Reveragen, NS Pharma, Fibrogen, Sarepta, Alexion, Janssen, and Argnx outside the submitted work. He also reports ad hoc consultancies for PTC therapeutics, WAVE Life Sciences, Edgewise, Epirium Bio, Janssen, Sarepta, and Regenxbio. All reimbursements were received by the LUMC. No personal financial benefit was received.T.V. has received consulting fees from BioMarin, Debiopharm, Dynacure, Italfarmaco, PTC Therapeutics, Sarepta Therapeutics, Santhera Antisense Therapeutics ,and Biophytis; he is an SAB member and holds equity in Constant Pharmaceuticals; he is a co-founder and holds equity in Dinaqor AG.; and is supported by the National Institute of Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust, and University College London.
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