[en] OBJECTIVE: Spinal muscular atrophy (SMA) is a common genetic cause of infant mortality. Nusinersen treatment ameliorates the clinical outcome of SMA, however, some patients respond well, while others have limited response. We investigated microRNAs in blood samples from SMA patients and their response to nusinersen treatment evaluating the potential of circulating microRNAs as biomarkers for SMA.
METHODS: In a discovery cohort study, microRNA next-generation sequencing was performed in blood samples from SMA patients (SMA type 2, n = 10; SMA type 3, n = 10) and controls (n = 7). The dysregulated microRNAs were further analysed in the therapeutic response cohort comprised of SMA type 1 patients (n = 22) who had received nusinersen treatment, at three time points along the treatment course (baseline, 2 and 6 months of treatment). The levels of the studied microRNAs were correlated to the SMA clinical outcome measures.
RESULTS: In the discovery cohort, 69 microRNAs were dysregulated between SMA patients and controls. In the therapeutic response cohort, the baseline plasma levels of miR-107, miR-142-5p, miR-335-5p, miR-423-3p, miR-660-5p, miR-378a-3p and miR-23a-3p were associated with the 2 and 6 months response to nusinersen treatment. Furthermore, the levels of miR-107, miR-142-5p, miR-335-5p, miR-423-3p, miR-660-5p and miR-378-3p at 2 months of treatment were associated with the response after 6 months of nusinersen treatment.
INTERPRETATION: Blood microRNAs could be used as biomarkers to indicate SMA patients' response to nusinersen and to monitor the efficacy of the therapeutic intervention. In addition, some of these microRNAs provide insight into processes involved in SMA that could be exploited as novel therapeutic targets.
Disciplines :
Neurology Pediatrics
Author, co-author :
Zaharieva, Irina T ; Developmental Neurosciences Research and Teaching Department, Dubowitz Neuromuscular Centre, Great Ormond Street Institute of Child Health, University College London, London, UK
Scoto, Mariacristina; Developmental Neurosciences Research and Teaching Department, Dubowitz Neuromuscular Centre, Great Ormond Street Institute of Child Health, University College London, London, UK ; Great Ormond Street Hospital, London, UK
Aragon-Gawinska, Karolina ; Institute I-Motion, Hôpital Armand Trousseau, Paris, France ; Neurology Department, Medical University of Warsaw, Warsaw, Poland
Ridout, Deborah; Population, Policy & Practice Department, UCL Great Ormond Street Institute of Child Health, London, UK ; NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK
Doreste, Bruno; Developmental Neurosciences Research and Teaching Department, Dubowitz Neuromuscular Centre, Great Ormond Street Institute of Child Health, University College London, London, UK
Servais, Laurent ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pédiatrie ; Institute I-Motion, Hôpital Armand Trousseau, Paris, France ; Department of Paediatrics, MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, UK
Muntoni, Francesco; Developmental Neurosciences Research and Teaching Department, Dubowitz Neuromuscular Centre, Great Ormond Street Institute of Child Health, University College London, London, UK ; Great Ormond Street Hospital, London, UK ; NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK
Zhou, Haiyan ; NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK ; Genetics and Genomic Medicine Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, UK
Language :
English
Title :
Response of plasma microRNAs to nusinersen treatment in patients with SMA.
The authors would like to thank the funding support from the National Institute of Health Research (NIHR) Biomedical Research Centre at Great Ormond Street Hospital and University College London (UCL), SMA Europe and Wellcome Trust (204841/Z/16/Z). The MRC Centre for Neuromuscular Diseases Biobank, supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital and UCL, is acknowledged for providing patients’ blood samples. The Muscular Dystrophy UK support to the Dubowitz Neuromuscular Centre and the Biogen support to the Neuromuscular Biobank are also gratefully acknowledged.The authors would like to thank the funding support from the National Institute of Health Research (NIHR) Biomedical Research Centre at Great Ormond Street Hospital and University College London (UCL), SMA Europe and Wellcome Trust (204841/Z/16/Z). The MRC Centre for Neuromuscular Diseases Biobank, supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital and UCL, is acknowledged for providing patients’ blood samples.The authors would like to thank the funding support from the National Institute of Health Research (NIHR) Biomedical Research Centre at Great Ormond Street Hospital and University College London (UCL), SMA Europe and Wellcome Trust (204841/Z/16/Z). The MRC Centre for Neuromuscular Diseases Biobank, supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital and UCL, is acknowledged for providing patients’ blood samples. The Muscular Dystrophy UK support to the Dubowitz Neuromuscular Centre and the Biogen support to the Neuromuscular Biobank are also gratefully acknowledged.F. Muntoni has received honoraria for presentation at meetings and scientific advisory boards of Biogen; Novartis and Roche. L. Servais, K. Aragon‐Gawinska received lecture honoraria and congress funding from Biogen and consultancy fees from Roche. No conflicts of interest from the other authors.
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