title: Development of MPS IVA mouse (Galnstm(hC79S.mC76S)slu) tolerant to human N-acetylgalactosamine-6-sulfate sulfatase.
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 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.
authors.affiliation: Department of Pediatrics, Pediatric Research Institute, Saint Louis University, MO 63110, USA. tomatsus@slu.edu
authors.forename: Shunji
authors.initials: S
authors.lastname: Tomatsu
authors.forename: Monica
authors.initials: M
authors.lastname: Gutierrez
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Nishioka
authors.forename: Masamichi
authors.initials: M
authors.lastname: Yamada
authors.forename: Mana
authors.initials: M
authors.lastname: Yamada
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tosaka
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Grubb
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Montaño
authors.forename: Matheus B
authors.initials: MB
authors.lastname: Vieira
authors.forename: Georgeta G
authors.initials: GG
authors.lastname: Trandafirescu
authors.forename: Olga M
authors.initials: OM
authors.lastname: Peña
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Koji O
authors.initials: KO
authors.lastname: Orii
authors.forename: Tadao
authors.initials: T
authors.lastname: Orii
authors.forename: Akihiko
authors.initials: A
authors.lastname: Noguchi
authors.forename: Leticia
authors.initials: L
authors.lastname: Laybauer
mesh_terms: D000818:Animals; D002811:Chondroitinsulfatases / Q000008:administration & dosage / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006351:Heart Valves / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D008099:Liver / Q000473:pathology; D008297:Male; D008578:Meninges / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009085:Mucopolysaccharidosis IV / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger
chemical_list: D012333:RNA, Messenger; D002811:Chondroitinsulfatases; C102295:GALNS protein, human; C491158:Galns protein, mouse