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Human Molecular Genetics Advance Access published online on October 11, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi364
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received June 2, 2005
Revised September 22, 2005
Accepted September 22, 2005

Article

Development of MPS IVA mouse (Galnstm(hC79S·mC76S)slu) tolerant to human N-acetylgalactosamine-6-sulfate sulfatase

Shunji Tomatsu 1*, Monica Gutierrez 2, Tatsuo Nishioka 2, Masamichi Yamada 3, Mana Yamada 3, Yasuhiro Tosaka 3, Jeffrey H. Grubb 4, Adriana M. Montaño 2, Matheus B. Vieira 2, Georgeta G. Trandafirescu 2, Olga M. Peña 2, Seiji Yamaguchi 5, Koji O. Orii 6, Tadao Orii 6, and Akihiko Noguchi 2

1 Department of Pediatrics, Saint Louis University Pediatric Research Institute, 3662 Park Ave. St. Louis, Missouri 63110-2586
2 Department of Pediatrics, Saint Louis University, Pediatric Research Institute, St. Louis, Missouri
3 JCR Phamaceuticals, Research Center, Asiya, Japan
4 Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, Missouri
5 Department of Pediatrics, Shimane University, Izumo, Japan
6 Department of Pediatrics, Gifu University, Gifu, Japan

* To whom correspondence should be addressed.
Shunji Tomatsu, E-mail: tomatsus{at}slu.edu


  Abstract

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disease caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency. In recent studies of enzyme replacement therapy for animal models with lysosomal storage diseases, cellular and humoral immune responses to the injected enzymes have been recognized as major impediments to effective treatment.

To study the long-term effectiveness and side effects of therapies in the absence of immune responses, we have developed an MPS IVA mouse model which has many similarities to human MPS IVA and is tolerant to human GALNS protein.

We used a construct containing both a transgene (cDNA) expressing inactive human GALNS in intron 1 and an active site mutation (C76S) in adjacent exon 2 and thereby introduced both the inactive cDNA and the C76S mutation into the murine Galns by targeted mutagenesis.

Affected homozygous mice have no detectable GALNS enzyme activity and accumulate GAGs in multiple tissues including visceral organs, brain, cornea, bone, ligament, and bone marrow. At 3 months, lysosomal storage is marked within hepatocytes, reticuloendothelial Kupffer cells, and cells of the sinusoidal lining of the spleen, neurons and meningeal cells. The bone storage is also obvious, with lysosomal distention in osteoblasts and osteocytes lining the cortical bone, in chondrocytes, and in the sinus lining cells in bone marrow. Ubiquitous expression of the inactive human GALNS was also confirmed by western blot using the anti-GALNS monoclonal antibodies newly produced, which resulted in tolerance to immune challenge with human enzyme.

The newly-generated MPS IVA mouse model should provide a good model to evaluate long-term administration of enzyme replacement.

Keywords: GALNS; mucopolysaccharidosis IVA; immune tolerance; targeted mutagenesis.
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S. Tomatsu, A. M. Montano, A. Ohashi, M. A. Gutierrez, H. Oikawa, T. Oguma, V. C. Dung, T. Nishioka, T. Orii, and W. S. Sly
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