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      Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial

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          Abstract

          SPR1NT ( NCT03505099) was a Phase III, multicenter, single-arm study to investigate the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated at ≤6 weeks of life. Here, we report final results for 14 children with two copies of SMN2, expected to develop spinal muscular atrophy (SMA) type 1. Efficacy was compared with a matched Pediatric Neuromuscular Clinical Research natural-history cohort ( n = 23). All 14 enrolled infants sat independently for ≥30 seconds at any visit ≤18 months (Bayley-III item #26; P < 0.001; 11 within the normal developmental window). All survived without permanent ventilation at 14 months as per protocol; 13 maintained body weight (≥3rd WHO percentile) through 18 months. No child used nutritional or respiratory support. No serious adverse events were considered related to treatment by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for children expected to develop SMA type 1, highlighting the urgency for universal newborn screening.

          Abstract

          For presymptomatic infants at risk for SMA type 1, onasemnogene abeparvovec improves motor outcomes, ventilator-free survival, and nutritional/respiratory independence compared with untreated or treated symptomatic patients

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          Most cited references56

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          Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy

          Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease.
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            Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes.

            Delivery of genes to the brain and spinal cord across the blood-brain barrier (BBB) has not yet been achieved. Here we show that adeno-associated virus (AAV) 9 injected intravenously bypasses the BBB and efficiently targets cells of the central nervous system (CNS). Injection of AAV9-GFP into neonatal mice through the facial vein results in extensive transduction of dorsal root ganglia and motor neurons throughout the spinal cord and widespread transduction of neurons throughout the brain, including the neocortex, hippocampus and cerebellum. In adult mice, tail vein injection of AAV9-GFP leads to robust transduction of astrocytes throughout the entire CNS, with limited neuronal transduction. This approach may enable the development of gene therapies for a range of neurodegenerative diseases, such as spinal muscular atrophy, through targeting of motor neurons, and amyotrophic lateral sclerosis, through targeting of astrocytes. It may also be useful for rapid postnatal genetic manipulations in basic neuroscience studies.
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              Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study

              Highlights • NURTURE is an ongoing study of nusinersen started in a presymptomatic stage of SMA. • All infants were ≥25 months old, and alive without permanent ventilation. • All infants achieved independent sitting and 88% (22/25) were walking alone. • Nusinersen demonstrated durability of effect with a median 2.9 years of follow up. • Nusinersen was well tolerated with no new safety concerns over extended follow up.
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                Author and article information

                Contributors
                kstrauss@clinicforspecialchildren.org
                Journal
                Nat Med
                Nat Med
                Nature Medicine
                Nature Publishing Group US (New York )
                1078-8956
                1546-170X
                17 June 2022
                17 June 2022
                : 1-9
                Affiliations
                [1 ]GRID grid.418640.f, Clinic for Special Children, ; Strasburg, PA USA
                [2 ]GRID grid.415783.c, ISNI 0000 0004 0418 2120, Penn Medicine-Lancaster General Hospital, ; Lancaster, PA USA
                [3 ]GRID grid.168645.8, ISNI 0000 0001 0742 0364, Departments of Pediatrics and Molecular, Cell & Cancer Biology, , University of Massachusetts School of Medicine, ; Worcester, MA USA
                [4 ]GRID grid.430417.5, ISNI 0000 0004 0640 6474, Department of Neurology, , Sydney Children’s Hospital Network, ; Sydney, New South Wales Australia
                [5 ]GRID grid.1005.4, ISNI 0000 0004 4902 0432, School of Clinical Medicine, , UNSW Medicine and Health, UNSW Sydney, ; Sydney, New South Wales Australia
                [6 ]GRID grid.83440.3b, ISNI 0000000121901201, The Dubowitz Neuromuscular Centre, , University College London, Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, ; London, UK
                [7 ]GRID grid.451056.3, ISNI 0000 0001 2116 3923, National Institute of Health Research, Great Ormond Street Hospital Biomedical Research Centre, ; London, UK
                [8 ]GRID grid.410818.4, ISNI 0000 0001 0720 6587, Institute of Medical Genetics, , Tokyo Women’s Medical University, ; Tokyo, Japan
                [9 ]GRID grid.240344.5, ISNI 0000 0004 0392 3476, Center for Gene Therapy, , Nationwide Children’s Hospital, ; Columbus, OH USA
                [10 ]GRID grid.261331.4, ISNI 0000 0001 2285 7943, Department of Pediatrics and Department of Neurology, , The Ohio State University, ; Columbus, OH USA
                [11 ]Department of Paediatrics, MDUK Oxford Neuromuscular Centre, Oxford, UK
                [12 ]GRID grid.4861.b, ISNI 0000 0001 0805 7253, Neuromuscular Reference Center, Department of Pediatrics, , CHU & University of Liège, ; Liège, Belgium
                [13 ]Departments of Pediatrics, Neurology & Neurosurgery, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Quebec Canada
                [14 ]GRID grid.428618.1, ISNI 0000 0004 0456 3687, Department of Pediatrics, , Nemours Children’s Hospital, ; Orlando, FL USA
                [15 ]GRID grid.240871.8, ISNI 0000 0001 0224 711X, Center for Experimental Neurotherapeutics, St. Jude Children’s Research Hospital, ; Memphis, TN USA
                [16 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Department of Neurology, , Massachusetts General Hospital, ; Boston, MA USA
                [17 ]GRID grid.14003.36, ISNI 0000 0001 2167 3675, Department of Neurology, , University of Wisconsin School of Medicine and Public Health, ; Madison, WI USA
                [18 ]GRID grid.4367.6, ISNI 0000 0001 2355 7002, Washington University School of Medicine, ; St. Louis, MO USA
                [19 ]GRID grid.239585.0, ISNI 0000 0001 2285 2675, Division of Pediatric Neurology, , Columbia University Medical Center, ; New York, NY USA
                [20 ]GRID grid.267313.2, ISNI 0000 0000 9482 7121, Department of Pediatrics, , University of Texas Southwestern Medical Center, ; Dallas, TX USA
                [21 ]GRID grid.413656.3, ISNI 0000 0004 0450 6121, Department of Neurology, , Helen DeVos Children’s Hospital, ; Grand Rapids, MI USA
                [22 ]GRID grid.430503.1, ISNI 0000 0001 0703 675X, Department of Pediatrics, , University of Colorado School of Medicine, ; Aurora, CO USA
                [23 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Department of Neurology, , David Geffen School of Medicine at UCLA, ; Los Angeles, CA USA
                [24 ]Novartis Gene Therapies, Inc., Bannockburn, IL USA
                [25 ]GRID grid.418424.f, ISNI 0000 0004 0439 2056, Translational Medicine, Novartis Institutes for BioMedical Research, ; Cambridge, MA USA
                Author information
                http://orcid.org/0000-0002-6429-8657
                http://orcid.org/0000-0002-4472-0902
                http://orcid.org/0000-0003-2632-0873
                http://orcid.org/0000-0001-9270-4061
                http://orcid.org/0000-0001-8927-2018
                http://orcid.org/0000-0002-9351-7054
                http://orcid.org/0000-0002-4593-6342
                http://orcid.org/0000-0003-0851-3516
                http://orcid.org/0000-0002-3552-7369
                http://orcid.org/0000-0001-7688-1818
                Article
                1866
                10.1038/s41591-022-01866-4
                9205281
                35715566
                4f080ac2-61ac-4eee-b014-d7dec8d676f9
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 18 February 2022
                : 10 May 2022
                Funding
                Funded by: Novartis Gene Therapies, Inc., sponsored this study.
                Categories
                Article

                Medicine
                gene therapy,development
                Medicine
                gene therapy, development

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