Abstract
Spinal muscular atrophy is an autosomal recessive neurodegenerative disorder characterized by progressive muscle wasting and loss of muscle function due to severe motor neuron dysfunction, secondary to mutations in the survival motor neuron 1 (SMN1) gene. A second neighboring centromeric gene, SMN2, is intact in all patients but contains a C-to-T variation in exon 7 that affects a splice enhancer and determines exclusion of exon 7 in the majority of its transcript, leading to an unstable protein that cannot substitute for mutant SMN1. Following successful studies on disease models and intensive studies on SMN functions in the past decade, SMN upregulation targeting SMN2, has been suggested as a possible therapeutic approach. Recently, we have witnessed an historical turning point with the first disease-modifying treatment receiving Food and Drug Administration approval and now being available to patients also outside the clinical trial. This innovative treatment is an antisense oligonucleotide, which, administered intrathecally, is able to increase exon 7 inclusion in the majority of the SMN2 mRNA and increase the production of fully functional SMN protein. Alternative advanced therapies, such as viral vector mediated gene therapy and orally available small molecules, are also showing promising results in early clinical trial phases.
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Acknowledgements
FM is supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. The MRC Centre for Neuromuscular Diseases Biobank and the support of the MDUK and of the SMA Trust to the activities of the Dubowitz Neuromuscular Centre is also gratefully acknowledged.
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FM is involved as principal investigator in the following clinical trials: nusinersen (SHINE, sponsored by Ionis and Biogen); olesoxime (OLEOS, sponsored by Roche). He has participated in scientific advisory board activities for Roche; Biogen and Avexis, and is also a member of the Pfizer rare disease scientific advisory board. MS is involved as sub-investigator in SHINE clinical trial and is principal investigator in OLEOS clinical trial. RFS is involved as principal investigator in the following SMA clinical trials: nusinersen (CS3A, ENDEAR, CHERISH, NURTURE and SHINE, sponsored by Ionis and Biogen) and CK-2127107 (CY 5021 study, sponsored by Cytokinetics and Astellas). He has participated in scientific advisory board activities for Ionis, Biogen, Roche, Novartis and AveXis; has served on the DSMB for the Roche RG7800 and AveXis AVXS-101 phase 1 study; and has served as an advisor to CureSMA (US), the SMA Foundation (US), SMA REACH (UK) and SMA Europe. EM is involved as principal investigator in the following clinical trials: nusinersen (SHINE, sponsored by Ionis and Biogen); olesoxime (OLEOS, sponsored by Roche). He has participated in scientific advisory board activities for Ionis, Roche; Biogen and Avexis.
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Scoto, M., Finkel, R., Mercuri, E. et al. Therapeutic approaches for spinal muscular atrophy (SMA). Gene Ther 24, 514–519 (2017). https://doi.org/10.1038/gt.2017.45
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DOI: https://doi.org/10.1038/gt.2017.45
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