Focal lesions following intracerebral gene therapy for mucopolysaccharidosis IIIA

Marianna Bugiani, Truus E.M. Abbink, Arthur W.D. Edridge, Lia van der Hoek, Anne E.J. Hillen, Niek P. van Til, Gino V. Hu-A-Ng, Marjolein Breur, Karen Aiach, Philippe Drevot, Michaël Hocquemiller, Ralph Laufer, Frits A. Wijburg, Marjo S. van der Knaap*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Objective: Mucopolysaccharidosis type IIIA (MPSIIIA) caused by recessive SGSH variants results in sulfamidase deficiency, leading to neurocognitive decline and death. No disease-modifying therapy is available. The AAVance gene therapy trial investigates AAVrh.10 overexpressing human sulfamidase (LYS-SAF302) delivered by intracerebral injection in children with MPSIIIA. Post-treatment MRI monitoring revealed lesions around injection sites. Investigations were initiated in one patient to determine the cause. Methods: Clinical and MRI details were reviewed. Stereotactic needle biopsies of a lesion were performed; blood and CSF were sampled. All samples were used for viral studies. Immunohistochemistry, electron microscopy, and transcriptome analysis were performed on brain tissue of the patient and various controls. Results: MRI revealed focal lesions around injection sites with onset from 3 months after therapy, progression until 7 months post therapy with subsequent stabilization and some regression. The patient had transient slight neurological signs and is following near-normal development. No evidence of viral or immunological/inflammatory cause was found. Immunohistochemistry showed immature oligodendrocytes and astrocytes, oligodendrocyte apoptosis, strong intracellular and extracellular sulfamidase expression and hardly detectable intracellular or extracellular heparan sulfate. No activation of the unfolded protein response was found. Interpretation: Results suggest that intracerebral gene therapy with local sulfamidase overexpression leads to dysfunction of transduced cells close to injection sites, with extracellular spilling of lysosomal enzymes. This alters extracellular matrix composition, depletes heparan sulfate, impairs astrocyte and oligodendrocyte function, and causes cystic white matter degeneration at the site of highest gene expression. The AAVance trial results will reveal the potential benefit–risk ratio of this therapy.

Original languageEnglish
Pages (from-to)904-917
Number of pages14
JournalAnnals of Clinical and Translational Neurology
Volume10
Issue number6
Early online date11 May 2023
DOIs
Publication statusPublished - Jun 2023

Bibliographical note

Funding Information:
We are grateful to the NIH NeuroBioBank (https://neurobiobank.nih.gov) for providing the tissue samples of the two untreated patients with MPSIIIA. We are grateful for the excellent execution of VIDISCA-NGS by Martin Deijs. We thank Prof. Eleonora Aronica (Amsterdam UMC, location AMC) for the tissue of control donors 3-5. We thank Prof. W. Peter Vandertop and Dr. Maarten Bot for their excellent work in the stereotactic brain biopsy.

Publisher Copyright:
© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Funding

We are grateful to the NIH NeuroBioBank (https://neurobiobank.nih.gov) for providing the tissue samples of the two untreated patients with MPSIIIA. We are grateful for the excellent execution of VIDISCA-NGS by Martin Deijs. We thank Prof. Eleonora Aronica (Amsterdam UMC, location AMC) for the tissue of control donors 3-5. We thank Prof. W. Peter Vandertop and Dr. Maarten Bot for their excellent work in the stereotactic brain biopsy.

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