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      Successful weaning from mechanical ventilation in a patient with SMA type 1 treated with nusinersen

      case-report

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          Abstract

          SMA type 1 is the most severe type, characterized by early onset at <6 months of age, and rapid progression resulting in permanent assisted ventilation before 2 years of life. Supportive care was the only treatment until the approval of nusinersen, an antisense oligonucleotide drug that increases functional SMN protein levels. We present a case of successful weaning from permanent ventilation via tracheostomy with nusinersen in an infant who had been diagnosed with SMA type 1 at the age of one month and had become ventilator‐dependent from the age of 3 months.

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          Most cited references17

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          Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

          New England Journal of Medicine, 377(18), 1723-1732
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            Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice.

            Survival of motor neuron 2, centromeric (SMN2) is a gene that modifies the severity of spinal muscular atrophy (SMA), a motor-neuron disease that is the leading genetic cause of infant mortality. Increasing inclusion of SMN2 exon 7, which is predominantly skipped, holds promise to treat or possibly cure SMA; one practical strategy is the disruption of splicing silencers that impair exon 7 recognition. By using an antisense oligonucleotide (ASO)-tiling method, we systematically screened the proximal intronic regions flanking exon 7 and identified two intronic splicing silencers (ISSs): one in intron 6 and a recently described one in intron 7. We analyzed the intron 7 ISS by mutagenesis, coupled with splicing assays, RNA-affinity chromatography, and protein overexpression, and found two tandem hnRNP A1/A2 motifs within the ISS that are responsible for its inhibitory character. Mutations in these two motifs, or ASOs that block them, promote very efficient exon 7 inclusion. We screened 31 ASOs in this region and selected two optimal ones to test in human SMN2 transgenic mice. Both ASOs strongly increased hSMN2 exon 7 inclusion in the liver and kidney of the transgenic animals. Our results show that the high-resolution ASO-tiling approach can identify cis-elements that modulate splicing positively or negatively. Most importantly, our results highlight the therapeutic potential of some of these ASOs in the context of SMA.
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              Nusinersen in patients older than 7 months with spinal muscular atrophy type 1: A cohort study

              To evaluate the safety and clinical efficacy of nusinersen in patients older than 7 months with spinal muscular atrophy type 1 (SMA1). Patients with SMA1 were treated with nusinersen by intrathecal injections as a part of the Expanded Access Program (EAP; NCT02865109 ). We evaluated patients before treatment initiation (M0) and at 2 months (M2) and 6 months (M6) after treatment initiation. Survival, respiratory, and nutritional data were collected. Motor function was assessed with the modified Hammersmith Infant Neurologic Examination Part 2 (HINE-2) and physiotherapist scales adjusted to patient age (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and the Motor Function Measure 20 or 32). We treated 33 children ranging in age from 8.3 to 113.1 months between December 2016 and May 2017. All patients were alive and were continuing treatment at M6. Median progress on the modified HINE-2 score was 1.5 points after 6 months of treatment ( p < 0.001). The need for respiratory support significantly increased over time. There were no statistically significant differences between patients presenting with 2 and those presenting with 3 copies of the survival motor neuron 2 ( SMN2 ) gene. Our results are in line with the phase 3 study for nusinersen in patients with SMA1 treated before 7 months of age and indicate that patients benefit from nusinersen even at a later stage of the disease. NCT02865109. This study provides Class IV evidence that for patients with SMA1 who are older than 7 months, nusinersen is beneficial.
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                Author and article information

                Contributors
                leejeehunmd@gmail.com
                Journal
                Ann Clin Transl Neurol
                Ann Clin Transl Neurol
                10.1002/(ISSN)2328-9503
                ACN3
                Annals of Clinical and Translational Neurology
                John Wiley and Sons Inc. (Hoboken )
                2328-9503
                22 February 2021
                April 2021
                : 8
                : 4 ( doiID: 10.1002/acn3.v8.4 )
                : 964-967
                Affiliations
                [ 1 ] Department of Pediatrics Samsung Medical Center Sungkyunkwan University School of Medicine Seoul Korea
                [ 2 ] Department of Pediatrics CHA Gangnam Medical Center CHA University Seoul Korea
                Author notes
                [*] [* ] Correspondence

                Jeehun Lee, Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon‐ro, Gangnam‐gu, Seoul 06351, Korea. Tel: +82‐2‐3410‐0910; Fax: +82‐2‐3410‐0043; E‐mail: jhlee0101@ 123456skku.edu ; leejeehunmd@ 123456gmail.com

                Article
                ACN351321
                10.1002/acn3.51321
                8045896
                33616311
                abf786c9-fbe4-4f26-b4b1-6c6ab9038090
                © 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 0, Tables: 2, Pages: 4, Words: 2537
                Product
                Categories
                Case Study
                Case Study
                Custom metadata
                2.0
                April 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:14.04.2021

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