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.
|
Authors | 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 |
Journal | Human gene therapy
(Hum Gene Ther)
Vol. 28
Issue 8
Pg. 626-638
(08 2017)
ISSN: 1557-7422 [Electronic] United States |
PMID | 28478695
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Glycosaminoglycans
- Iduronate Sulfatase
|
Topics |
- Animals
- Central Nervous System
(metabolism)
- Cognition
- Dependovirus
(genetics)
- Disease Models, Animal
- Enzyme Activation
- Female
- Gene Expression
- Gene Order
- Gene Transfer Techniques
- Genetic Therapy
- Genetic Vectors
(administration & dosage, genetics)
- Glycosaminoglycans
(metabolism)
- Humans
- Iduronate Sulfatase
(blood, genetics, metabolism)
- Male
- Mice
- Mucopolysaccharidosis II
(blood, genetics, psychology, therapy)
- Neuropsychological Tests
- Pilot Projects
- Time Factors
- Tissue Distribution
- Transduction, Genetic
|