title: Enzyme replacement therapy in newborn mucopolysaccharidosis IVA mice: early treatment rescues bone lesions?
abstract: We treated mucopolysaccharidosis IVA (MPS IVA) mice to assess the effects of long-term enzyme replacement therapy (ERT) initiated at birth, since adult mice treated by ERT showed little improvement in bone pathology [1]. To conduct ERT in newborn mice, we used recombinant human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) produced in a CHO cell line. First, to observe the tissue distribution pattern, a dose of 250units/g body weight was administered intravenously in MPS IVA mice at day 2 or 3. The infused enzyme was primarily recovered in the liver and spleen, with detectable activity in the bone and brain. Second, newborn ERT was conducted after a tissue distribution study. The first injection of newborn ERT was performed intravenously, the second to fourth weekly injections were intraperitoneal, and the remaining injections from 5th to 14th weeks were intravenous into the tail vein. MPS IVA mice treated with GALNS showed clearance of lysosomal storage in the liver and spleen, and sinus lining cells in bone marrow. The column structure of the growth plate was organized better than that in adult mice treated with ERT; however, hyaline and fibrous cartilage cells in the femur, spine, ligaments, discs, synovium, and periosteum still had storage materials to some extent. Heart valves were refractory to the treatment. Levels of serum keratan sulfate were kept normal in newborn ERT mice. In conclusion, the enzyme, which enters the cartilage before the cartilage cell layer becomes mature, prevents disorganization of column structure. Early treatment from birth leads to partial remission of bone pathology in MPS IVA mice.
authors: Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA. Electronic address: stomatsu@nemours.org.
authors: Shunji
authors: S
authors: Tomatsu
authors: Department of Pediatrics, Saint Louis University Doisy Research Center, St. Louis, MO, USA; Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors: Adriana M
authors: AM
authors: Montaño
authors: Suzuka University of Medical Science, School of Pharmacy, Japan.
authors: Hirotaka
authors: H
authors: Oikawa
authors: Department of Endocrinology, Metabolism & Genetics, Vietnam National Hospital of Pediatrics, Hanoi, Viet Nam.
authors: Vu Chi
authors: VC
authors: Dung
authors: Myojinshita Aoki Dermatology Clinic, Tokyo, Japan.
authors: Amiko
authors: A
authors: Hashimoto
authors: Daiichi-Sankyo Pharmaceutical Co., Tokyo, Japan.
authors: Toshihiro
authors: T
authors: Oguma
authors: Department of Pediatrics, Saint Louis University Doisy Research Center, St. Louis, MO, USA.
authors: Monica L
authors: ML
authors: Gutiérrez
authors: Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
authors: Tatsuo
authors: T
authors: Takahashi
authors: Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
authors: Tsutomu
authors: T
authors: Shimada
authors: Department of Pediatrics, Gifu University, School of Medicine, Gifu, Japan.
authors: Tadao
authors: T
authors: Orii
authors: Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors: William S
authors: WS
authors: Sly
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000831:Animals, Newborn; D001847:Bone Diseases / Q000188:drug therapy* / Q000473:pathology; D016466:CHO Cells; D002356:Cartilage / Q000187:drug effects / Q000648:ultrastructure; D019902:Chondrocytes / Q000187:drug effects / Q000648:ultrastructure; D002811:Chondroitinsulfatases / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003412:Cricetulus; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy; D006132:Growth Plate / Q000187:drug effects / Q000648:ultrastructure; D007632:Keratan Sulfate / Q000097:blood; D008099:Liver / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009085:Mucopolysaccharidosis IV / Q000188:drug therapy* / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D013154:Spleen / Q000187:drug effects; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D011994:Recombinant Proteins; D007632:Keratan Sulfate; D002811:Chondroitinsulfatases; C102295:GALNS protein, human
keywords: Enzyme replacement therapy; Fibrous cartilage; Hyaline cartilage; Mucopolysaccharidosis IVA; N-acetylgalactosamine-6-sulfate sulfatase