Rescue of neurologic disease in mucopolysaccharidosis type II mice via AAV-mediated liver delivery of brain-penetrating iduronate-2-sulfatase.

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.