Natural history of infantile-onset spinal muscular atrophy.
Stephen J. Kolb,Christopher S. Coffey,Jon W. Yankey,Kristin J. Krosschell,W. David Arnold,Seward B. Rutkove,Kathryn J. Swoboda,Sandra P. Reyna,Ai Sakonju,Basil T. Darras,Richard Shell,Nancy L. Kuntz,Diana Castro,Julie A. Parsons,Anne M. Connolly,Claudia A. Chiriboga,Craig M. McDonald,W. Bryan Burnette,Klaus Werner,Mathula Thangarajh,Perry B. Shieh,Erika Finanger,Merit Cudkowicz,Michelle McGovern,D. Elizabeth McNeil,Richard S. Finkel,Susan T. Iannaccone,Edward M. Kaye,Allison Kingsley,Samantha R. Renusch,Vicki L. McGovern,Xueqian Wang,Phillip G. Zaworski,Thomas W. Prior,Arthur H.M. Burghes,Amy Bartlett,John T. Kissel +36 more
TLDR
Clinical trials in infantile‐onset spinal muscular atrophy require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes.Abstract:
OBJECTIVE Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. METHODS A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed. RESULTS Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post-hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17). INTERPRETATION These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real-world," prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883-891.read more
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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.
Darryl C. De Vivo,Enrico Bertini,Kathryn J. Swoboda,Wuh-Liang Hwu,Thomas O. Crawford,Richard S. Finkel,Janbernd Kirschner,Nancy L. Kuntz,Julie A. Parsons,Monique M. Ryan,Russell J. Butterfield,Haluk Topaloglu,Tawfeg Ben-Omran,Valeria A. Sansone,Yuh-Jyh Jong,Francy Shu,John F. Staropoli,Douglas A. Kerr,Alfred Sandrock,Christopher Stebbins,Marco Petrillo,Gabriel Braley,Kristina Johnson,Richard Foster,Sarah Gheuens,Ishir Bhan,Sandra P. Reyna,Stephanie Fradette,Wildon Farwell +28 more
TL;DR: Interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial emphasize the importance of proactive treatment with nusineren immediately after establishing the genetic diagnosis of SMA in presymptic infants and emerging newborn screening efforts.
Journal ArticleDOI
Gene therapy for neurological disorders: progress and prospects
Benjamin E. Deverman,Benjamin E. Deverman,Bernard Ravina,Krystof S. Bankiewicz,Steven M. Paul,Dinah W. Y. Sah +5 more
TL;DR: Key considerations and challenges in the future design and development of therapeutic AAV vectors are discussed, highlighting the most promising targets and recent clinical advances.
Journal ArticleDOI
Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial.
John W. Day,Richard S. Finkel,Claudia A. Chiriboga,Anne M. Connolly,Thomas O. Crawford,Basil T. Darras,Susan T. Iannaccone,Nancy L. Kuntz,Loren D M Pena,Loren D M Pena,Perry B. Shieh,Edward C. Smith,Jennifer M. Kwon,Craig M. Zaidman,Meredith Schultz,Douglas E. Feltner,Sitra Tauscher-Wisniewski,Haojun Ouyang,Deepa H. Chand,Deepa H. Chand,Douglas M. Sproule,Thomas A Macek,Jerry R. Mendell,Jerry R. Mendell +23 more
TL;DR: Onasemnogene abeparvovec (previously known as AVXS-101) is a gene therapy delivering the survival motor neuron gene (SMN) in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy as discussed by the authors.
Journal ArticleDOI
Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies
Basil T. Darras,Claudia A. Chiriboga,Susan T. Iannaccone,Kathryn J. Swoboda,Jacqueline Montes,Laurence Mignon,Shuting Xia,C. Frank Bennett,Kathie M. Bishop,Jeremy M. Shefner,Allison M. Green,Peng Sun,Ishir Bhan,Sarah Gheuens,Eugene Schneider,Wildon Farwell,Darryl C. De Vivo +16 more
TL;DR: Nusinersen treatment over ∼3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts, document the long-term benefit of nusineren in later-onset SMA, including SMA type III.
Journal ArticleDOI
Clinical trials, progression-speed differentiating features and swiftness rule of the innovative targets of first-in-class drugs.
Ying Hong Li,Xiao Xu Li,Xiao Xu Li,Jia Jun Hong,Yun Xia Wang,Jian Bo Fu,Hong Yang,Chun Yan Yu,Feng Cheng Li,Jie Hu,Weiwei Xue,Yuyang Jiang,Yu Zong Chen,Feng Zhu,Feng Zhu +14 more
TL;DR: A comprehensive analysis of all 89 innovative targets of first-in-class drugs approved in 2004–17 confirmed the literature-reported common druggability characteristics for clinical success of these innovative targets, exposed trial-speed differentiating features associated to the on-target and off-target collateral effects in humans and revealed a simple rule for identifying the speedy human targets through clinical trials.
References
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Journal ArticleDOI
A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy
TL;DR: 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.
Journal ArticleDOI
Correlation between severity and SMN protein level in spinal muscular atrophy.
Suzie Lefebvre,Philippe Burlet,Qing Liu,Solange Bertrandy,Olivier Clermont,Arnold Munnich,Gideon Dreyfuss,Judith Melki +7 more
TL;DR: A marked deficiency of the SMN protein in SMA is shown and the molecular mechanism underlying the pathogenesis of the disease is elucidated by western blot and immunohistochemical analyses using antibodies raised against theSMN protein.
Journal ArticleDOI
A Single Nucleotide Difference That Alters Splicing Patterns Distinguishes the SMA Gene SMN1 From the Copy Gene SMN2
Umrao R. Monani,Christian L. Lorson,D. William Parsons,Thomas W. Prior,Elliot J. Androphy,Arthur H.M. Burghes,John Douglas Mcpherson +6 more
TL;DR: This study completely sequenced and compared genomic clones containing the SMN genes and suggests that the exon 7 nucleotide change affects the activity of an exon splice enhancer which causes SMA.
Journal ArticleDOI
Quantitative Analyses of SMN1 and SMN2 Based on Real-Time LightCycler PCR: Fast and Highly Reliable Carrier Testing and Prediction of Severity of Spinal Muscular Atrophy
TL;DR: A new, fast, and highly reliable quantitative test, based on real-time LightCycler PCR that amplifies either SMN1 or SMN2, which calculates the posterior probability that a child with homozygous absence ofSMN1 will develop type I, type II, or type III SMA.
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