Comparative dose effectiveness of intravenous and intrathecal AAV9.CB7.hIDS, RGX-121, in a murine model of mucopolysaccharidosis type II

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 leaves neurological disease unaddressed. 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 (IT) and intravenous (IV) routes of administration (ROA) at a range of vector doses in a mouse model of MPS II. While lower doses were completely ineffective, a total dose of 1x10⁹gc resulted in appreciable IDS activity levels in plasma, but not tissues. Total doses of 1x10¹⁰gc and 1x10¹¹gc 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 1x10¹¹gc IT achieved the highest IDS activity levels, greatest reduction in GAG content, and prevented neurocognitive deficiency. We conclude that a dose of 1x10¹⁰gc normalized metabolic and skeletal outcomes, while neurologic improvement required a dose of 1x10¹¹gc, thereby suggesting the prospect of a similar direct benefit in humans.