Effects of gene replacement therapy with resamirigene bilparvovec (AT132) on skeletal muscle pathology in X-linked myotubular myopathy: results from a substudy of the ASPIRO open-label clinical trial

Michael W. Lawlor, Medical College of Wisconsin, Department of Pathology and Laboratory Medicine, Milwaukee, WI, 53226, USA; Diverge Translational Science Laboratory, Milwaukee, WI, 53204, USA. Electronic address: mlawlor@divergetsl.com.
Benedikt Schoser, Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilian University of Munich, 80336, Germany.
Marta Margeta, Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA.
Caroline A. Sewry, Wolfson Centre of Inherited Neuromuscular Disorders, RJAH Orthopaedic Hospital, Oswestry, SY10 7AG, UK; Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital for Children, 30 Guilford Street, London, WC1N 1EH, UK.
Karra A. Jones, Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.
Perry B. Shieh, Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles, CA, 90095, USA.
Nancy L. Kuntz, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, 60611, USA.
Barbara K. Smith, Department of Physical Therapy, University of Florida, Gainesville, FL, 32610-0154, USA.
James J. Dowling, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
Wolfgang Müller-Felber, Dr. von Hauner Children's Hospital, Klinikum der Universität München, 80337, Munich, Germany.
Carsten G. Bönnemann, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda, MD, 20892-1477, USA.
Andreea M. Seferian, I-Motion, Hôpital Armand Trousseau, 75571, Paris, France.
Astrid Blaschek, Dr. von Hauner Children's Hospital, Klinikum der Universität München, 80337, Munich, Germany.
Sarah Neuhaus, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda, MD, 20892-1477, USA.
A Reghan Foley, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda, MD, 20892-1477, USA.
Dimah N. Saade, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda, MD, 20892-1477, USA.
Etsuko Tsuchiya, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
Ummulwara R. Qasim, Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles, CA, 90095, USA.
Margaret Beatka, Medical College of Wisconsin, Department of Pathology and Laboratory Medicine, Milwaukee, WI, 53226, USA; Diverge Translational Science Laboratory, Milwaukee, WI, 53204, USA.
Mariah J. Prom, Medical College of Wisconsin, Department of Pathology and Laboratory Medicine, Milwaukee, WI, 53226, USA; Diverge Translational Science Laboratory, Milwaukee, WI, 53204, USA.
Emily Ott, Medical College of Wisconsin, Department of Pathology and Laboratory Medicine, Milwaukee, WI, 53226, USA; Diverge Translational Science Laboratory, Milwaukee, WI, 53204, USA.
Susan Danielson, Medical College of Wisconsin, Department of Pathology and Laboratory Medicine, Milwaukee, WI, 53226, USA.
Paul Krakau, Medical College of Wisconsin, Department of Pathology and Laboratory Medicine, Milwaukee, WI, 53226, USA; Diverge Translational Science Laboratory, Milwaukee, WI, 53204, USA.
Suresh N. Kumar, Medical College of Wisconsin, Department of Pathology and Laboratory Medicine, Milwaukee, WI, 53226, USA.
Hui Meng, Medical College of Wisconsin, Department of Pathology and Laboratory Medicine, Milwaukee, WI, 53226, USA; Diverge Translational Science Laboratory, Milwaukee, WI, 53204, USA.
Mark Vanden Avond, Medical College of Wisconsin, Department of Pathology and Laboratory Medicine, Milwaukee, WI, 53226, USA.
Clive Wells, Medical College of Wisconsin, Department of Pathology and Laboratory Medicine, Milwaukee, WI, 53226, USA.
Heather Gordish-Dressman, Children's National Hospital and George Washington University School of Medicine and Health Sciences Department of Pediatrics, Washington, DC, 20037, USA.
Alan H. Beggs, Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Sarah Christensen, Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.), San Francisco, CA, 94108, USA.
Edward Conner, Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.), San Francisco, CA, 94108, USA.
Emma S. James, Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.), San Francisco, CA, 94108, USA.

Document Type

Journal Article

Publication Date

12-11-2023

Journal

EBioMedicine

Volume

99

DOI

10.1016/j.ebiom.2023.104894

Keywords

Adeno-associated viral vector; Centronuclear myopathy; Gene replacement therapy; Human; Pathology; X-linked myotubular myopathy

Abstract

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated. METHODS: Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed. FINDINGS: Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants. INTERPRETATION: Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study. FUNDING: Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).

Department

Genomics and Precision Medicine

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