Abstract
Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disease caused by iduronate-2-sulfatase (IDS) deficiency, leading to accumulation of glycosaminoglycans (GAGs) and the emergence of progressive disease. Enzyme replacement therapy is the only currently approved treatment, but it leaves neurological disease unaddressed. Cerebrospinal fluid (CSF)-directed administration of AAV9.CB7.hIDS (RGX-121) is an alternative treatment strategy, but it is unknown if this approach will affect both neurologic and systemic manifestations. We compared the effectiveness of intrathecal (i.t.) and intravenous (i.v.) routes of administration (ROAs) at a range of vector doses in a mouse model of MPS II. While lower doses were completely ineffective, a total dose of 1 × 109 gc resulted in appreciable IDS activity levels in plasma but not tissues. Total doses of 1 × 1010 and 1 × 1011 gc by either ROA resulted in supraphysiological plasma IDS activity, substantial IDS activity levels and GAG reduction in nearly all tissues, and normalized zygomatic arch diameter. In the brain, a dose of 1 × 1011 gc i.t. achieved the highest IDS activity levels and the greatest reduction in GAG content, and it prevented neurocognitive deficiency. We conclude that a dose of 1 × 1010 gc normalized metabolic and skeletal outcomes, while neurologic improvement required a dose of 1 × 1011 gc, thereby suggesting the prospect of a similar direct benefit in humans.