INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy.

Autor:	Dowling JJ; Hospital for Sick Children, Toronto, Canada., Müller-Felber W; Dr. v. Haunersches Kinderspital, Klinikum der Universität München, Munich, Germany., Smith BK; University of Florida, Gainesville, FL, USA., Bönnemann CG; National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA., Kuntz NL; Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA., Muntoni F; National Institute for Health Research (NIHR) Great Ormond Street (GOS) Hospital Biomedical Research Centre, University College London Institute of Child Health, London, UK., Servais L; I-Motion, Hôpital Armand Trousseau, Paris, France.; Division of Child Neurology, Reference Center for Neuromuscular Diseases, Department of Pediatrics, University Hospital Liège & University of Liège, Belgium., Alfano LN; Nationwide Children's Hospital, Columbus, OH, USA., Beggs AH; Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Bilder DA; University of Utah, Salt Lake City, UT, USA., Blaschek A; Dr. v. Haunersches Kinderspital, Klinikum der Universität München, Munich, Germany., Duong T; Stanford University, Palo Alto, CA, USA., Graham RJ; Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Jain M; NIH Hatfield Clinical Research Center, Bethesda, MD, USA., Lawlor MW; Medical College of Wisconsin, Milwaukee, WI, USA., Lee J; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA., Coats J; Astellas Gene Therapies (formerly Audentes Therapeutics), San Francisco, CA, USA., Lilien C; I-Motion, Hôpital Armand Trousseau, Paris, France., Lowes LP; Nationwide Children's Hospital, Columbus, OH, USA., MacBean V; Brunel University London, London, UK and King's College 32 London, London, UK., Neuhaus S; National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA., Noursalehi M; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA., Pitts T; University of Louisville, Louisville, KY, USA., Finlay C; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA.; University of Louisville, Louisville, KY, USA., Christensen S; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA.; University of Louisville, Louisville, KY, USA., Rafferty G; King's College London, London, UK., Seferian AM; I-Motion, Hôpital Armand Trousseau, Paris, France., Tsuchiya E; Hospital for Sick Children, Toronto, Canada., James ES; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA.; University of Louisville, Louisville, KY, USA., Miller W; Astellas Gene Therapies (formerly Audentes Therapeutics), San Francisco, CA, USA., Sepulveda B; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA., Vila MC; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA., Prasad S; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA., Rico S; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA., Shieh PB; University of California, Los Angeles, CA, USA.
Jazyk:	angličtina
Zdroj:	Journal of neuromuscular diseases [J Neuromuscul Dis] 2022; Vol. 9 (4), pp. 503-516.
DOI:	10.3233/JND-210781
Abstrakt:	Background: X-linked myotubular myopathy (XLMTM) is a life-threatening congenital myopathy that, in most cases, is characterized by profound muscle weakness, respiratory failure, need for mechanical ventilation and gastrostomy feeding, and early death. Objective: We aimed to characterize the neuromuscular, respiratory, and extramuscular burden of XLMTM in a prospective, longitudinal study. Methods: Thirty-four participants < 4 years old with XLMTM and receiving ventilator support enrolled in INCEPTUS, a prospective, multicenter, non-interventional study. Disease-related adverse events, respiratory and motor function, feeding, secretions, and quality of life were assessed. Results: During median (range) follow-up of 13.0 (0.5, 32.9) months, there were 3 deaths (aspiration pneumonia; cardiopulmonary failure; hepatic hemorrhage with peliosis) and 61 serious disease-related events in 20 (59%) participants, mostly respiratory (52 events, 18 participants). Most participants (80%) required permanent invasive ventilation (>16 hours/day); 20% required non-invasive support (6-16 hours/day). Median age at tracheostomy was 3.5 months (95% CI: 2.5, 9.0). Thirty-three participants (97%) required gastrostomy. Thirty-one (91%) participants had histories of hepatic disease and/or prospectively experienced related adverse events or laboratory or imaging abnormalities. CHOP INTEND scores ranged from 19-52 (mean: 35.1). Seven participants (21%) could sit unsupported for≥30 seconds (one later lost this ability); none could pull to stand or walk with or without support. These parameters remained static over time across the INCEPTUS cohort. Conclusions: INCEPTUS confirmed high medical impact, static respiratory, motor and feeding difficulties, and early death in boys with XLMTM. Hepatobiliary disease was identified as an under-recognized comorbidity. There are currently no approved disease-modifying treatments.
Databáze:	MEDLINE
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