Focal lesions following intracerebral gene therapy for mucopolysaccharidosis IIIA.
Marianna BugianiTruus E M AbbinkArthur W D EdridgeLia van der HoekAnne E J HillenNiek P van TilGino V Hu-A-NgMarjolein BreurKaren AiachPhilippe DrevotMichaël HocquemillerRalph LauferFrits A WijburgMarjo S van der KnaapPublished in: Annals of clinical and translational neurology (2023)
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.
Keyphrases
- extracellular matrix
- gene therapy
- gene expression
- white matter
- genome wide
- induced apoptosis
- dna methylation
- cell cycle arrest
- study protocol
- replacement therapy
- oxidative stress
- copy number
- single cell
- transcription factor
- ultrasound guided
- randomized controlled trial
- stem cells
- climate change
- human health
- bone marrow
- mesenchymal stem cells