Stephen J Kolb1,2, Christopher S Coffey3, Jon W Yankey3, Kristin Krosschell4, W David Arnold1,5, Seward B Rutkove6, Kathryn J Swoboda7,8, Sandra P Reyna7,9, Ai Sakonju7,10, Basil T Darras8, Richard Shell11, Nancy Kuntz12, Diana Castro13, Julie Parsons14, Anne M Connolly15, Claudia A Chiriboga16, Craig McDonald17, W Bryan Burnette18, Klaus Werner10, Mathula Thangarajh19, Perry B Shieh20, Erika Finanger21, Merit E Cudkowicz22, Michelle M McGovern22, D Elizabeth McNeil9,23, Richard Finkel24, Susan T Iannaccone13, Edward Kaye25, Allison Kingsley1, Samantha R Renusch2, Vicki L McGovern2, Xueqian Wang2, Phillip G Zaworski26, Thomas W Prior27, Arthur H M Burghes2, Amy Bartlett1, John T Kissel1. 1. Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH. 2. Department of Biological Chemistry & Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH. 3. Department of Biostatistics, NeuroNEXT Data Coordinating Center, University of Iowa, Iowa City, IA. 4. Departments of Physical Therapy and Human Movement Sciences and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL. 5. Department of Physical Medicine and Rehabilitation, The Ohio State University Wexner Medical Center, Columbus, OH. 6. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA. 7. Departments of Neurology and Pediatrics, University of Utah, Salt Lake City, UT. 8. Department of Neurology, Boston Children's Hospital, Boston, MA. 9. Biogen, Boston, MA. 10. SUNY Upstate Medical Center, Syracuse, NY. 11. Nationwide Children's Hospital, Columbus, OH. 12. Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL. 13. UT Southwestern Medical Center, Dallas, TX. 14. Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO. 15. Washington University School of Medicine in St. Louis, St. Louis, MO. 16. Department of Neurology, Columbia College of Physicians and Surgeons, New York, NY. 17. University of California-Davis, Davis, CA. 18. Vanderbilt University, Nashville, TN. 19. Children's National Medical Center, Washington, DC. 20. University of California-Los Angeles, Los Angeles, CA. 21. Dorenbecher Children's Hospital, Portland, OR. 22. Department of Neurology, NeuroNEXT Clinical Coordinating Center, Massachusetts General Hospital, Boston, MA. 23. National Institute of Neurological Disorders and Stroke, Bethesda, MD. 24. Nemours Children's Hospital, Orlando, FL. 25. Sarepta Therapeutics, Cambridge, MA. 26. PharmOptima, Portage, MI. 27. Department of Molecular Pathology, Ohio State Wexner Medical Center, Columbus, OH.
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.
OBJECTIVE: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infantmortality, 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.
Authors: S Bernal; L Alías; M J Barceló; E Also-Rallo; R Martínez-Hernández; J Gámez; E Guillén-Navarro; J Rosell; I Hernando; F J Rodríguez-Alvarez; S Borrego; J M Millán; C Hernández-Chico; M Baiget; P Fuentes-Prior; E F Tizzano Journal: J Med Genet Date: 2010-06-24 Impact factor: 6.318
Authors: Chitra Iyer; Xueqian Wang; Samantha R Renusch; Sandra I Duque; Allison M Wehr; Xiaokui-Molly Mo; Vicki L McGovern; W David Arnold; Arthur H M Burghes; Stephen J Kolb Journal: J Neuromuscul Dis Date: 2017
Authors: P E McAndrew; D W Parsons; L R Simard; C Rochette; P N Ray; J R Mendell; T W Prior; A H Burghes Journal: Am J Hum Genet Date: 1997-06 Impact factor: 11.025
Authors: Aga Lewelt; Kristin J Krosschell; Charles Scott; Ai Sakonju; John T Kissel; Thomas O Crawford; Gyula Acsadi; Guy D'anjou; Bakri Elsheikh; Sandra P Reyna; Mary K Schroth; Jo Anne Maczulski; Gregory J Stoddard; Elie Elovic; Kathryn J Swoboda Journal: Muscle Nerve Date: 2010-11 Impact factor: 3.217
Authors: Sandra I Duque; W David Arnold; Philipp Odermatt; Xiaohui Li; Paul N Porensky; Leah Schmelzer; Kathrin Meyer; Stephen J Kolb; Daniel Schümperli; Brian K Kaspar; Arthur H M Burghes Journal: Ann Neurol Date: 2015-02-09 Impact factor: 10.422
Authors: Ching H Wang; Richard S Finkel; Enrico S Bertini; Mary Schroth; Anita Simonds; Brenda Wong; Annie Aloysius; Leslie Morrison; Marion Main; Thomas O Crawford; Anthony Trela Journal: J Child Neurol Date: 2007-08 Impact factor: 1.987
Authors: Petra Kaufmann; Michael P McDermott; Basil T Darras; Richard S Finkel; Douglas M Sproule; Peter B Kang; Maryam Oskoui; Andrei Constantinescu; Clifton L Gooch; A Reghan Foley; Michele L Yang; Rabi Tawil; Wendy K Chung; William B Martens; Jacqueline Montes; Vanessa Battista; Jessica O'Hagen; Sally Dunaway; Jean Flickinger; Janet Quigley; Susan Riley; Allan M Glanzman; Maryjane Benton; Patricia A Ryan; Mark Punyanitya; Megan J Montgomery; Jonathan Marra; Benjamin Koo; Darryl C De Vivo Journal: Neurology Date: 2012-10-17 Impact factor: 9.910
Authors: Stephen J Kolb; Christopher S Coffey; Jon W Yankey; Kristin Krosschell; W David Arnold; Seward B Rutkove; Kathryn J Swoboda; Sandra P Reyna; Ai Sakonju; Basil T Darras; Richard Shell; Nancy Kuntz; Diana Castro; Susan T Iannaccone; Julie Parsons; Anne M Connolly; Claudia A Chiriboga; Craig McDonald; W Bryan Burnette; Klaus Werner; Mathula Thangarajh; Perry B Shieh; Erika Finanger; Merit E Cudkowicz; Michelle M McGovern; D Elizabeth McNeil; Richard Finkel; Edward 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 Journal: Ann Clin Transl Neurol Date: 2016-01-21 Impact factor: 4.511
Authors: Phillip Zaworski; Katharine M von Herrmann; Shannon Taylor; Sara S Sunshine; Kathleen McCarthy; Nicole Risher; Tara Newcomb; Marla Weetall; Thomas W Prior; Kathryn J Swoboda; Karen S Chen; Sergey Paushkin Journal: PLoS One Date: 2016-03-08 Impact factor: 3.240
Authors: Benjamin E Deverman; Bernard M Ravina; Krystof S Bankiewicz; Steven M Paul; Dinah W Y Sah Journal: Nat Rev Drug Discov Date: 2018-08-10 Impact factor: 84.694
Authors: Merit Cudkowicz; Marianne K Chase; Christopher S Coffey; Dixie J Ecklund; Brenda J Thornell; Codrin Lungu; Katy Mahoney; Laurie Gutmann; Jeremy M Shefner; Kevin J Staley; Michael Bosch; Eric Foster; Jeffrey D Long; Emine O Bayman; James Torner; Jon Yankey; Richard Peters; Trevis Huff; Robin A Conwit; Shlomo Shinnar; Donna Patch; Basil T Darras; Audrey Ellis; Roger J Packer; Karen S Marder; Claudia A Chiriboga; Claire Henchcliffe; Joyce Ann Moran; Blagovest Nikolov; Stewart A Factor; Carole Seeley; Steven M Greenberg; Anthony A Amato; Sara DeGregorio; Tanya Simuni; Tina Ward; John T Kissel; Stephen J Kolb; Amy Bartlett; Joseph F Quinn; Kellie Keith; Steven R Levine; Nadege Gilles; Patricia K Coyle; Jessica Lamb; Gil I Wolfe; Annemarie Crumlish; Luis Mejico; Muhammad Maaz Iqbal; James D Bowen; Caryl Tongco; Louis B Nabors; Khurram Bashir; Melanie Benge; Craig M McDonald; Erik K Henricson; Björn Oskarsson; Bruce H Dobkin; Catherine Canamar; Tracy A Glauser; Daniel Woo; Angela Molloy; Peggy Clark; Timothy L Vollmer; Alexander J Stein; Richard J Barohn; Mazen M Dimachkie; Jean-Baptiste Le Pichon; Michael G Benatar; Julie Steele; Lawrence Wechsler; Paula R Clemens; Christine Amity; Robert G Holloway; Christine Annis; Mark P Goldberg; Mariam Andersen; Susan T Iannaccone; A Gordon Smith; J Robinson Singleton; Mariana Doudova; E Clarke Haley; Mark S Quigg; Stephanie Lowenhaupt; Beth A Malow; Karen Adkins; David B Clifford; Mengesha A Teshome; Noreen Connolly Journal: JAMA Neurol Date: 2020-06-01 Impact factor: 18.302