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      Safety, Tolerability, and Effect of Nusinersen Treatment in Ambulatory Adults With 5q-SMA


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          Objective: To determine the safety and tolerability of nusinersen treatment in ambulatory adults with spinal muscular atrophy (SMA) and investigate the treatment effect on muscle strength, physical function, and motor unit physiology.

          Methods: Individuals aged 18 years or older with genetically confirmed 5q SMA, three or more copies of the SMN2 gene, and the ability to ambulate 30 feet were enrolled. Safety outcomes included the number of adverse events and serious adverse events, clinically significant vital sign or laboratory parameter abnormalities. Outcome assessments occurred at baseline (prior to the first dose of nusinersen) and then 2, 6, 10, and 14 months post-treatment.

          Results: Six women, seven men (mean age: 37 ± 11, range: 18–59 years) were included for analyses. The most common side effects were headache and back pain, but overall procedures and treatments were well-tolerated. No serious adverse events were reported. Maximal Voluntary Isometric Muscle Contraction Testing (MVICT) and 6-min walk test (6MWT) both showed overall stability with significant increases at 2, 6, and 10 months for the 6MWT. More consistent significant treatment effects were noted on the Hammersmith Functional Motor Scale Expanded, SMA-Functional Rating Scale, and forced vital capacity. Treatment resulted in progressively increased ulnar compound muscle action potential and average single motor unit potential amplitudes, but motor unit number estimation remained stable.

          Conclusions: Nusinersen treatment is safe and well-tolerated in ambulatory adults with SMA. Treatment resulted in improved motor function and electrophysiological findings suggest that this improvement may be occurring via improved motor unit reinnervation capacity.

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          Most cited references31

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          Identification and characterization of a spinal muscular atrophy-determining gene

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            Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study.

            Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy.
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              A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy.

              SMN1 and SMN2 (survival motor neuron) encode identical proteins. A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA). Analysis of transcripts from SMN1/SMN2 hybrid genes and a new SMN1 mutation showed a direct relationship between presence of disease and exon 7 skipping. We have reported previously that the exon-skipped product SMNDelta7 is partially defective for self-association and SMN self-oligomerization correlated with clinical severity. To evaluate systematically which of the five nucleotides that differ between SMN1 and SMN2 effect alternative splicing of exon 7, a series of SMN minigenes was engineered and transfected into cultured cells, and their transcripts were characterized. Of these nucleotide differences, the exon 7 C-to-T transition at codon 280, a translationally silent variance, was necessary and sufficient to dictate exon 7 alternative splicing. Thus, the failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer. These findings demonstrate the molecular genetic basis for the nature and pathogenesis of SMA and illustrate a novel disease mechanism. Because individuals with SMA retain the SMN2 allele, therapy targeted at preventing exon 7 skipping could modify clinical outcome.

                Author and article information

                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                20 May 2021
                : 12
                [1] 1Department of Neurology, The Ohio State University Wexner Medical Center , Columbus, OH, United States
                [2] 2Department of Anesthesiology, The Ohio State University Wexner Medical Center , Columbus, OH, United States
                [3] 3Department of Biomedical Informatics and Center for Biostatistics, The Ohio State University , Columbus, OH, United States
                [4] 4Assistive Technology Department, The Ohio State University Wexner Medical Center , Columbus, OH, United States
                Author notes

                Edited by: Giuseppe Piscosquito, Ospedali Riuniti San Giovanni di Dio e Ruggi D'Aragona, Italy

                Reviewed by: Gerald Pfeffer, University of Calgary, Canada; Jacqueline Montes, Columbia University Irving Medical Center, United States

                *Correspondence: Bakri Elsheikh bakri.elsheikh@ 123456osumc.edu

                This article was submitted to Neuromuscular Disorders and Peripheral Neuropathies, a section of the journal Frontiers in Neurology

                Copyright © 2021 Elsheikh, Severyn, Zhao, Kline, Linsenmayer, Kelly, Tellez, Bartlett, Heintzman, Reynolds, Sterling, Weaver, Rajneesh, Kolb and Arnold.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 0, Tables: 3, Equations: 0, References: 32, Pages: 7, Words: 5354
                Funded by: Biogen 10.13039/100005614
                Funded by: Cure SMA 10.13039/100007721
                Original Research

                ambulatory,spinal muscular atrophy,nusinersen,motor unit,reinnervation
                ambulatory, spinal muscular atrophy, nusinersen, motor unit, reinnervation


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