Non-invasive intravenous administration of AAV9 transducing iduronate sulfatase leads to global metabolic correction and prevention of neurologic deficits in a mouse model of Hunter syndrome

Kanut Laoharawee; Kelly M Podetz-Pedersen; Tam T Nguyen; Sajya M Singh; Miles C Smith; Lalitha R Belur; Walter C Low; Karen F Kozarsky; R Scott McIvor

doi:10.1016/j.ymgmr.2023.100956

Non-invasive intravenous administration of AAV9 transducing iduronate sulfatase leads to global metabolic correction and prevention of neurologic deficits in a mouse model of Hunter syndrome

Mol Genet Metab Rep. 2023 Jan 20:34:100956. doi: 10.1016/j.ymgmr.2023.100956. eCollection 2023 Mar.

Authors

Kanut Laoharawee¹, Kelly M Podetz-Pedersen¹, Tam T Nguyen¹, Sajya M Singh¹, Miles C Smith¹, Lalitha R Belur¹, Walter C Low², Karen F Kozarsky³, R Scott McIvor¹

Affiliations

¹ Center for Genome Engineering, Department of Genetics Cell Biology and Development, 6-160 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455, USA.
² Department of Neurosurgery; University of Minnesota, Minneapolis, USA.
³ REGENXBIO Inc., Rockville, MD, USA.

Abstract

Hunter syndrome is a rare x-linked recessive genetic disorder that affects lysosomal metabolism due to deficiency of iduronate-2-sulfatase (IDS), with subsequent accumulation of glycosaminoglycans heparan and dermatan sulfates (GAG). Enzyme replacement therapy is the only FDA-approved remedy and is an expensive life-time treatment that alleviates some symptoms of the disease without neurocognitive benefit. We previously reported successful treatment in a mouse model of mucopolysaccharidosis type II (MPS II) using adeno-associated viral vector serotype 9 encoding human IDS (AAV9.hIDS) via intracerebroventricular injection. As a less invasive and more straightforward procedure, here we report intravenously administered AAV9.hIDS in a mouse model of MPS II. In animals administered 1.5 × 10¹² vg of AAV9.hIDS at 2 months of age, we observed supraphysiological levels of IDS enzyme activity in the circulation (up to 9100-fold higher than wild-type), in the tested peripheral organs (up to 560-fold higher than wild-type), but only 4% to 50% of wild type levels in the CNS. GAG levels were normalized on both sides of the blood-brain-barrier (BBB) in most of tissues tested. Despite low levels of the IDS observed in the CNS, this treatment prevented neurocognitive decline as shown by testing in the Barnes maze and by fear conditioning. This study demonstrates that a single dose of IV-administered AAV9.hIDS may be an effective and non-invasive procedure to treat MPS II that benefits both sides of the BBB, with implications for potential use of IV-administered AAV9 for other neuronopathic lysosomal diseases.

Keywords: Gene therapy; Gene transfer; Hunter syndrome; MPS II; Metabolic disorder; Mucopolysaccharidosis type II.