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 journalArticle

10 Citations (Scopus)

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 1 2017

Fingerprint

Iduronate Sulfatase
Mucopolysaccharidosis II
Central Nervous System
Genes
Glycosaminoglycans
Dermatan Sulfate
Dependovirus
Injections
Hepatomegaly
Heparitin Sulfate
United States Food and Drug Administration
Nervous System Diseases
Nervous System
Brain
Enzymes
Therapeutics

Keywords

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

Cite this

Prevention of neurocognitive deficiency in mucopolysaccharidosis Type II mice by central nervous system-directed, AAV9-mediated iduronate sulfatase gene transfer. / Laoharawee, Kanut; Podetz-Pedersen, Kelly M.; Nguyen, Tam T.; Evenstar, Laura B.; Kitto, Kelley F.; Nan, Zhenhong; Fairbanks, Carolyn A.; Low, Walter C.; Kozarsky, Karen F.; Mcivor, R. Scott.

In: Human gene therapy, Vol. 28, No. 8, 01.08.2017, p. 626-638.

Research output: Contribution to journalArticle

@article{ec7ae72e4d4b47b7a3b22e403c2507ce,
title = "Prevention of neurocognitive deficiency in mucopolysaccharidosis Type II mice by central nervous system-directed, AAV9-mediated iduronate sulfatase gene transfer",
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.",
keywords = "AAV, Hunter syndrome, gene therapy, mucopolysaccharidosis type II, neurocognitive function",
author = "Kanut Laoharawee and Podetz-Pedersen, {Kelly M.} and Nguyen, {Tam T.} and Evenstar, {Laura B.} and Kitto, {Kelley F.} and Zhenhong Nan and Fairbanks, {Carolyn A.} and Low, {Walter C.} and Kozarsky, {Karen F.} and Mcivor, {R. Scott}",
year = "2017",
month = "8",
day = "1",
doi = "10.1089/hum.2016.184",
language = "English (US)",
volume = "28",
pages = "626--638",
journal = "Human Gene Therapy",
issn = "1043-0342",
publisher = "Mary Ann Liebert Inc.",
number = "8",

}

TY - JOUR

T1 - Prevention of neurocognitive deficiency in mucopolysaccharidosis Type II mice by central nervous system-directed, AAV9-mediated iduronate sulfatase gene transfer

AU - Laoharawee, Kanut

AU - Podetz-Pedersen, Kelly M.

AU - Nguyen, Tam T.

AU - Evenstar, Laura B.

AU - Kitto, Kelley F.

AU - Nan, Zhenhong

AU - Fairbanks, Carolyn A.

AU - Low, Walter C.

AU - Kozarsky, Karen F.

AU - Mcivor, R. Scott

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

KW - AAV

KW - Hunter syndrome

KW - gene therapy

KW - mucopolysaccharidosis type II

KW - neurocognitive function

UR - http://www.scopus.com/inward/record.url?scp=85027396799&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85027396799&partnerID=8YFLogxK

U2 - 10.1089/hum.2016.184

DO - 10.1089/hum.2016.184

M3 - Article

VL - 28

SP - 626

EP - 638

JO - Human Gene Therapy

JF - Human Gene Therapy

SN - 1043-0342

IS - 8

ER -