Prevention of neurocognitive deficiency in mucopolysaccharidosis Type II mice by central nervous system-directed, AAV9-mediated iduronate sulfatase gene transfer

Kanut Laoharawee, Kelly M. Podetz-Pedersen, Tam T. Nguyen, Laura B. Evenstar, Kelley F. Kitto, Zhenhong Nan, Carolyn A. Fairbanks, Walter C. Low, Karen F. Kozarsky, R. Scott Mcivor

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare X-linked recessive lysosomal disorder caused by defective iduronate-2-sulfatase (IDS), resulting in accumulation of heparan sulfate and dermatan sulfate glycosaminoglycans (GAGs). Enzyme replacement is the only Food and Drug Administration-approved therapy available for MPS II, but it is expensive and does not improve neurologic outcomes in MPS II patients. This study evaluated the effectiveness of adeno-associated virus (AAV) vector encoding human IDS delivered intracerebroventricularly in a murine model of MPS II. Supraphysiological levels of IDS were observed in the circulation (160-fold higher than wild type) for at least 28 weeks post injection and in most tested peripheral organs (up to 270-fold) at 10 months post injection. In contrast, only low levels of IDS were observed (7-40% of wild type) in all areas of the brain. Sustained IDS expression had a profound effect on normalization of GAG in all tested tissues and on prevention of hepatomegaly. Additionally, sustained IDS expression in the central nervous system (CNS) had a prominent effect in preventing neurocognitive deficit in MPS II mice treated at 2 months of age. This study demonstrates that CNS-directed, AAV9 mediated gene transfer is a potentially effective treatment for Hunter syndrome, as well as other monogenic disorders with neurologic involvement.

Original languageEnglish (US)
Pages (from-to)626-638
Number of pages13
JournalHuman gene therapy
Volume28
Issue number8
DOIs
StatePublished - Aug 2017

Keywords

  • AAV
  • Hunter syndrome
  • gene therapy
  • mucopolysaccharidosis type II
  • neurocognitive function

Fingerprint Dive into the research topics of 'Prevention of neurocognitive deficiency in mucopolysaccharidosis Type II mice by central nervous system-directed, AAV9-mediated iduronate sulfatase gene transfer'. Together they form a unique fingerprint.

Cite this