SMN2 protein, human; Survival of Motor Neuron 2 Protein; Child; Humans; Infant; Survival of Motor Neuron 2 Protein/genetics; Muscular Atrophy, Spinal/genetics; Spinal Muscular Atrophies of Childhood/genetics; Spinal Muscular Atrophies of Childhood/therapy; Muscular Atrophy, Spinal; Spinal Muscular Atrophies of Childhood; Biochemistry, Genetics and Molecular Biology (all); General Biochemistry, Genetics and Molecular Biology; General Medicine
Abstract :
[en] Most children with biallelic SMN1 deletions and three SMN2 copies develop spinal muscular atrophy (SMA) type 2. SPR1NT ( NCT03505099 ), a Phase III, multicenter, single-arm trial, investigated the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated within six postnatal weeks. Of 15 children with three SMN2 copies treated before symptom onset, all stood independently before 24 months (P < 0.0001; 14 within normal developmental window), and 14 walked independently (P < 0.0001; 11 within normal developmental window). All survived without permanent ventilation at 14 months; ten (67%) maintained body weight (≥3rd WHO percentile) without feeding support through 24 months; and none required nutritional or respiratory support. No serious adverse events were considered treatment-related by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for presymptomatic infants at risk of SMA type 2, underscoring the urgency of early identification and intervention.
Disciplines :
Neurology Pediatrics
Author, co-author :
Strauss, Kevin A ; Clinic for Special Children, Strasburg, PA, USA. kstrauss@clinicforspecialchildren.org ; Penn Medicine-Lancaster General Hospital, Lancaster, PA, USA. kstrauss@clinicforspecialchildren.org ; Departments of Pediatrics and Molecular, Cell & Cancer Biology, University of Massachusetts School of Medicine, Worcester, MA, USA. kstrauss@clinicforspecialchildren.org
Farrar, Michelle A ; Department of Neurology, Sydney Children's Hospital Network, Sydney, NSW, Australia ; School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Sydney, NSW, Australia
Muntoni, Francesco; The Dubowitz Neuromuscular Centre, University College London, Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK ; National Institute of Health Research, Great Ormond Street Hospital Biomedical Research Centre, London, UK
Saito, Kayoko ; Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan
Mendell, Jerry R; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA ; Department of Pediatrics and Department of Neurology, The Ohio State University, Columbus, OH, USA
Servais, Laurent ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pédiatrie ; Department of Paediatrics, MDUK Oxford Neuromuscular Centre, Oxford, UK
McMillan, Hugh J ; Department of Pediatrics, Neurology & Neurosurgery, Montreal Children's Hospital, McGill University, Montreal, QC, Canada
Finkel, Richard S ; Department of Pediatrics, Nemours Children's Hospital, Orlando, FL, USA ; Center for Experimental Neurotherapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA
Swoboda, Kathryn J ; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
Kwon, Jennifer M; Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
Zaidman, Craig M; Washington University School of Medicine, St. Louis, MO, USA
Chiriboga, Claudia A; Division of Pediatric Neurology, Columbia University Medical Center, New York, NY, USA
Iannaccone, Susan T ; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
Krueger, Jena M; Department of Neurology, Helen DeVos Children's Hospital, Grand Rapids, MI, USA
Parsons, Julie A; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
Shieh, Perry B; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Kavanagh, Sarah; Novartis Gene Therapies, Inc., Bannockburn, IL, USA
Wigderson, Melissa; Novartis Gene Therapies, Inc., Bannockburn, IL, USA
Tauscher-Wisniewski, Sitra; Novartis Gene Therapies, Inc., Bannockburn, IL, USA
McGill, Bryan E ; Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, MA, USA
Macek, Thomas A ; Novartis Gene Therapies, Inc., Bannockburn, IL, USA
The authors wish to thank the investigators, site coordinators, and study teams, administrators of newborn screening programs and, most importantly, the patients, families, and caregivers for their participation in these studies. The authors also thank M. Milton of Novartis Institutes for Biomedical Research, who provided critical review and input on content related to biodistribution, immune response and safety; S. P. Reyna of Novartis Gene Therapies, Inc., who provided critical review and input on SMA patient care; and M. Wolf of Novartis Gene Therapies, Inc., who provided functional outcome measure expertise and contributions to study conduct and oversight. Medical writing assistance and editorial support was provided by J. Gibson from Kay Square Scientific and M. Nissen of Novartis Gene Therapies, Inc. This support was funded by Novartis Gene Therapies, Inc. The NSW Pilot NBS study was funded by Luminesce Alliance, a not-for-profit cooperative joint venture across the Sydney Children’s Hospital Network, Children’s Medical Research Institute, and Children’s Cancer Institute, established with the support of the New South Wales Government. Luminesce Alliance is also affiliated with UNSW Sydney and The University of Sydney. The SPR1NT study was designed and funded by Novartis Gene Therapies, Inc., which was involved in the study design, data collection, data analysis, data interpretation, and writing of all related reports and publications.The authors wish to thank the investigators, site coordinators, and study teams, administrators of newborn screening programs and, most importantly, the patients, families, and caregivers for their participation in these studies. The authors also thank M. Milton of Novartis Institutes for Biomedical Research, who provided critical review and input on content related to biodistribution, immune response and safety; S. P. Reyna of Novartis Gene Therapies, Inc., who provided critical review and input on SMA patient care; and M. Wolf of Novartis Gene Therapies, Inc., who provided functional outcome measure expertise and contributions to study conduct and oversight. Medical writing assistance and editorial support was provided by J. Gibson from Kay Square Scientific and M. Nissen of Novartis Gene Therapies, Inc. This support was funded by Novartis Gene Therapies, Inc. The NSW Pilot NBS study was funded by Luminesce Alliance, a not-for-profit cooperative joint venture across the Sydney Children’s Hospital Network, Children’s Medical Research Institute, and Children’s Cancer Institute, established with the support of the New South Wales Government. Luminesce Alliance is also affiliated with UNSW Sydney and The University of Sydney. The SPR1NT study was designed and funded by Novartis Gene Therapies, Inc., which was involved in the study design, data collection, data analysis, data interpretation, and writing of all related reports and publications.Novartis Gene Therapies, Inc. sponsored this clinical trial. The authors declare the following competing interests. K.A.S. has received personal compensation from Novartis Gene Therapies, Inc. (formerly AveXis, Inc.) for serving as an advisory board member and from Biogen for serving as a visiting professor, and has received research support from clinical trials sponsored by Novartis Gene Therapies, Inc., and Biogen. M.A.F. has received honoraria for scientific advisory boards from Novartis Gene Therapies, Inc., Biogen, and Roche and research grants from Biogen. F.M. reports grants and personal fees from Novartis Gene Therapies, Inc., including participation in the STR1VE-EU grant and the SPR1NT study; grants, personal fees, and other (participation in the SHINE clinical trial and principal investigator of the investigator-initiated UK SMA REACH UK registry) from Biogen; and grants and personal fees from Roche, including participation in the JEWELFISH clinical trial of risdiplam and participation in the olesoxime clinical trial, during the conduct of the study. F.M. has also received honoraria for scientific advisory boards from Biogen, Novartis, Novartis Gene Therapies, Inc., PTC, Roche, and Sarepta Therapeutics. K.S. has served on advisory boards for Biogen, Novartis Gene Therapies, Inc./Novartis, and Chugai (Roche) and has received search funding from Biogen. J.R.M. has received personal compensation for clinical trial consulting and for serving on scientific advisory boards, as well as research support, from Novartis Gene Therapies, Inc. L.S. has received personal compensation as an advisory committee board member/consultant from Novartis Gene Therapies, Inc., Biogen, Biophytis, Cytokinetics, Dynacure, Roche, Santhera, and Sarepta Therapeutics, and has received research support from Novartis Gene Therapies, Inc., Biogen, Dynacure, and Roche. H.J.M. has received honoraria for scientific advisory boards from Novartis Gene Therapies, Inc., and has received research funding from Roche. R.S.F. has received personal compensation for advisory board participation from Novartis Gene Therapies, Inc., Biogen, Roche, and Scholar Rock, and for consulting from Novartis; editorial fees from Elsevier for co-editing a neurology textbook; license fees from the Children’s Hospital of Philadelphia; and research funding from Novartis Gene Therapies, Inc., Biogen, Roche/Genentech, and Scholar Rock. K.J.S. has received personal compensation for a speaking engagement from Biogen, and research funding as a principal investigator for clinical trials sponsored by Novartis Gene Therapies, Inc. and Biogen. J.M.K. was site principal investigator for clinical trials sponsored by Novartis Gene Therapies, Inc., Biogen, and Scholar Rock. C.M.Z. has received research support from Biogen. C.A.C. has served on advisory boards for Novartis Gene Therapies, Inc., and Roche/Genentech; has served as an educational speaker for Biogen; and has received research funding from Novartis Gene Therapies, Inc., Biogen, and Roche. S.T.I. has received personal compensation for service on advisory boards or consulting from Novartis Gene Therapies, Inc., Biogen, Roche/Genentech, and Sarepta Therapeutics; and research support from Novartis Gene Therapies, Inc., Biogen, Capricor, PTC, Scholar Rock, and Sarepta Therapeutics. J.M.K. is a principal investigator for clinical trials sponsored by Novartis Gene Therapies, Inc., Scholar Rock, and Roche/Genentech. J.A.P. has served as an investigator on clinical trials for Biogen, Novartis, PTC Therapeutics, and Scholar Rock, and has served in an advisory capacity for Biogen, Scholar Rock, Roche/Genentech, and Novartis. P.B.S. has served as a consultant for Alexion, Biogen, Genentech, Novartis Gene Therapies, Inc., and Sarepta and has served as a speaker for Alexion, Biogen, Genentech, Grifols, Novartis Gene Therapies, Inc., and PTC Therapeutics. S.K. is an employee of Novartis Gene Therapies, Inc., and receives consulting fees from UCB Pharma, Karuna Therapeutics, Worldwide Clinical Trials, CPC Clinical Research, Zosano Pharmaceuticals, PharPoint Research, and Nesos, Inc. M.W. is an employee of Novartis Gene Therapies, Inc., and owns Novartis stock or other equities. S.T.-W. is an employee of Novartis Gene Therapies, Inc., and owns Novartis stock or other equities. B.E.M. is an employee of Translational Medicine, Novartis Institutes for BioMedical Research (Cambridge), and owns Novartis stock or other equities. T.A.M. is an employee of Novartis Gene Therapies, Inc., and owns Novartis stock or other equities. Novartis Gene Therapies, Inc., sponsored this study.
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