Abstract: Applicants sought to express human iduronate-2-sulfatase (hIDS) in the brain endothelium of a mouse model of Mucopolysaccharidosis type II (MPSII, Hunter's syndrome) to enable enzyme secretion into the brain parenchyma. In this disorder, IDS deficiency results in the pathophysiological accumulation of heparan and dermatan sulfate GAGs. To test the hypothesis, Applicants chose AAV-BI30, an AAV9-derived capsid that has an enhanced in vivo tropism specific to the endothelium in the rodent CNS and can transduce human brain vascular endothelial cells in vitro more efficiently than AAV9. Applicants show that systemic delivery of AAV-BI30: hIDS restored IDS enzyme activity in the brain, liver, and serum of IDS-KO mice (FIG. 1). Importantly, AAV-BI30-mediated gene transfer resulted in the correction of GAG accumulation in the brain (FIG. 2). This effect was not observed when using the AAV-BI30 vector packaging a non-secreting version of hIDS.