Effects of sulfatide on peripheral nerves in metachromatic leukodystrophy
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To evaluate the longitudinal correlations between sulfatide/lysosulfatide levels and central and peripheral nervous system function in children with metachromatic leukodystrophy (MLD) and to explore the impact of intravenous recombinant human arylsulfatase A (rhASA) treatment on myelin turnover.
Methods
A Phase 1/2 study of intravenous rhASA investigated cerebrospinal fluid (CSF) and sural nerve sulfatide levels, 88-item Gross Motor Function Measure (GMFM-88) total score, sensory and motor nerve conduction, brain N-acetylaspartate (NAA) levels, and sural nerve histology in 13 children with MLD. Myelinated and unmyelinated nerves from an untreated MLD mouse model were also analyzed.
Results
CSF sulfatide levels correlated with neither Z-scores for GMFM-88 nor brain NAA levels; however, CSF sulfatide levels correlated negatively with Z-scores of nerve conduction parameters, number of large (≥7 μm) myelinated fibers, and myelin/fiber diameter slope, and positively with nerve g-ratios and cortical latencies of somatosensory-evoked potentials. Quantity of endoneural litter positively correlated with sural nerve sulfatide/lysosulfatide levels. CSF sulfatide levels decreased with continuous high-dose treatment; this change correlated with improved nerve conduction. At 26 weeks after treatment, nerve g-ratio decreased by 2%, and inclusion bodies per Schwann cell unit increased by 55%. In mice, abnormal sulfatide storage was observed in non-myelinating Schwann cells in Remak bundles of sciatic nerves but not in unmyelinated urethral nerves.
Interpretation
Lower sulfatide levels in the CSF and peripheral nerves correlate with better peripheral nerve function in children with MLD; intravenous rhASA treatment may reduce CSF sulfatide levels and enhance sulfatide/lysosulfatide processing and remyelination in peripheral nerves.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Annals of Clinical and Translational Neurology |
| Vol/bind | 11 |
| Udgave nummer | 2 |
| Sider (fra-til) | 328-341 |
| Antal sider | 14 |
| ISSN | 2328-9503 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
This study was funded by Shire (a Takeda company). Under the direction of the authors and in accordance with the International Committee of Medical Journal Editors Uniform Requirements, Emma Davies PhD of Oxford PharmaGenesis, Oxford, UK provided writing assistance for this manuscript. Editorial assistance in formatting, proofreading, copy editing, and fact‐checking was also provided by Oxford PharmaGenesis, and funded by Takeda Development Center Americas, Inc. The sponsor was involved in the study design, but data collection, analysis, and interpretation were made by the authors independently. The authors would like to thank Volkmar Gieselmann for his provision of the MLD mouse models and insightful feedback on the mouse electron microscopy data, and John W. Griffin (Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA), who made a valuable contribution to the ultrastructural analyses and who sadly passed away in 2011.
Funding Information:
M.H.F. has nothing to disclose. C.D. reports personal fees from University Hospital Copenhagen Rigshospitalet during the conduct of the study. S.G. reports an institutional research grant from Shire (a Takeda company) outside of the submitted work. He serves as an adviser for trials in MLD for Clario, Homology Medicines, and Passage Bio, but receives no personal payment related to this role. S.G. is a member of the European Reference Network for Rare Neurological Diseases, project ID 739510, and was partly supported by DFG grant GR 4688/2‐1. M.M. has nothing to disclose. D.A.H.W. is a full‐time employee of Takeda and a stockholder of Takeda Pharmaceutical Company Limited. C.J.M. is a full‐time employee of Takeda and a stockholder of Takeda Pharmaceutical Company Limited. I.K.‐M. reports grants from Shire (a Takeda company) during the conduct of the study. J.L. was a full‐time employee of Takeda and a stockholder of Takeda Pharmaceutical Company Limited at the time of the study. N.B. was a full‐time employee of Takeda and a stockholder of Takeda Pharmaceutical Company Limited at the time of the study. C.K. reports grants and personal fees from Shire (a Takeda company) and grants from Danish Medical Research during the conduct of the study. C.K. has also received royalties for teaching chapters from Gyldenal and FADL publishers.
Publisher Copyright:
© 2023 Takeda Development Center Americas, Inc. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
ID: 379254525