Human Molecular Genetics Advance Access originally published online on October 11, 2005
Human Molecular Genetics 2005 14(22):3321-3335; doi:10.1093/hmg/ddi364
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Development of MPS IVA mouse (Galnstm(hC79S·mC76S)slu) tolerant to human N-acetylgalactosamine-6-sulfate sulfatase
1Department of Pediatrics and 2Department of Biochemistry and Molecular Biology, Pediatric Research Institute, Saint Louis University, St. Louis, Missouri, USA, 3Department of Pediatrics, Shimane University, Izumo, Japan, 4Department of Pediatrics, Gifu University, Gifu, Japan and 5JCR Pharmaceuticals, Research Center, Asiya, Japan
* To whom correspondence should be addressed at: Department of Pediatrics, Pediatric Research Institute, Saint Louis University, 3662 Park Avenue, St. Louis, MO 63110-2586, USA. Tel: +1 3145775623 ext. 6213; Fax: +1 3145775398; Email: tomatsus{at}slu.edu
Received June 2, 2005; Accepted September 22, 2005
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 glycosaminoglycans 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.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
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