ArticleNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics2025
Rescue of neurologic disease in mucopolysaccharidosis type II mice via AAV-mediated liver delivery of brain-penetrating iduronate-2-sulfatase.
Article in Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Advances in Therapies for Mucopolysaccharidoses.Current issues in molecular biology · 2026Review
- Commentary: Lysosomal enzymes engineered to cross the blood-brain barrier are reshaping the therapeutic landscape of neuronopathic mucopolysaccharidoses.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
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Authors and funding
16 authors.
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Abstract
Mucopolysaccharidosis type II (MPS II) is a neurodegenerative lysosomal storage disorder (LSD) caused by inherited mutations in the iduronate-2-sulfatase (IDS) gene. Approximately two-thirds of patients exhibit severe central nervous system (CNS) involvement and cognitive impairment, which remain unaddressed by conventional enzyme replacement therapy (ERT) due to the inability of wild-type IDS to cross the blood-brain barrier (BBB). To overcome this limitation, we engineered a brain-penetrant IDS variant, eBT-IDS4, which retained enzymatic activity and demonstrated enhanced BBB transcytosis in vitro. We then evaluated a liver-directed gene therapy approach using an adeno-associated virus 8 (AAV8) vector encoding eBT-IDS4 under the control of a liver-specific promoter (LSP) in an adult MPS II mouse model. Intravenous administration of AAV8.LSP.IVS2.eBT-IDS4 resulted in sustained supraphysiological IDS activity and normalization of glycosaminoglycan (GAG) levels in peripheral tissues. Notably, this strategy achieved 89 % of wild-type IDS activity in the brain, leading to complete correction of neuropathology and reversal of cognitive deficits in 8-month-old MPS II mice. These findings support a promising, minimally invasive gene therapy strategy for treating MPS II and other neurodegenerative LSDs.
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