ArticleAnnals of clinical and translational neurology2023
Focal lesions following intracerebral gene therapy for mucopolysaccharidosis IIIA.
Article in Annals of clinical and translational neurology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 9 citations in OpenAlex.
- Safety considerations of gene-based therapies for Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Advances in Therapies for Mucopolysaccharidoses.Current issues in molecular biology · 2026Review
- AAV Kills Dividing Cells by Depleting PARP1 and Other DNA Damage Response Proteins.bioRxiv : the preprint server for biology · 2025Article
- Metachromatic Leukodystrophy: New Therapy Advancements and Emerging Research Directions.Neurology · 2025Review
- Delivery of Adeno-Associated Virus Vectors to the Central Nervous System for Correction of Single Gene Disorders.International journal of molecular sciences · 2024Review
- Gene and Cellular Therapies for Leukodystrophies.Pharmaceutics · 2023Review
- Transplantation of Wild-Type Hematopoietic Stem and Progenitor Cells Improves Disease Phenotypes in a Mucopolysaccharidosis IIIC Mouse Model.Cell transplantationArticle
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectiveMucopolysaccharidosis 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.
methodsClinical 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.
resultsMRI 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.
interpretationResults 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.
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