title: Enzyme replacement therapy on hypophosphatasia mouse model.
abstract: Hypophosphatasia (HPP) is an inborn error of metabolism caused by deficiency of the tissue-nonspecific alkaline phosphatase (TNSALP), resulting in a defect of bone mineralization. Natural substrates for this ectoenzyme accumulate extracellulary including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5-phosphate (PLP), a co-factor form of vitamin B6. Enzyme replacement therapy (ERT) for HPP by functional TNSALP is one of the therapeutic options. The C-terminal-anchorless human recombinant TNSALP derived from Chinese hamster ovary cell lines was purified. TNSALP-null mice (Akp2 (-/-) ), an infantile model of HPP, were treated from birth using TNSALP and vitamin B6 diet. Long-term efficacy studies of ERT consisted of every 3 days subcutaneous or intravenous injections till 28 days old (dose 20 U/g) and subsequently every 3 days intravenous injections for 6 months (dose 10 U/g). We assessed therapeutic effect by growth and survival rates, fertility, skeletal manifestations, and radiographic and pathological finding. Treated Akp2 (-/-) mice grew normally till 4 weeks and appeared well with a minimum skeletal abnormality as well as absence of epilepsy, compared with untreated mice which died by 3 weeks old. The prognosis of TNSALP-treated Akp2 (-/-) mice was improved substantially: 1) prolonged life span over 6 months, 2) improvement of the growth, and 3) normal fertility. After 6 months of treatment, we found moderate hypomineralization with abnormal proliferative chondrocytes in growth plate and articular cartilage. In conclusion, ERT with human native TNSALP improves substantial clinical manifestations in Akp2 (-/-) mice, suggesting that ERT with anchorless TNSALP is also a potential therapy for HPP.
authors: Growth, Development and Metabolism Program, Singapore Institute for Clinical Sciences, Wilmington, DE.
authors: Hirotaka
authors: H
authors: Oikawa
authors: Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE.
authors: Shunji
authors: S
authors: Tomatsu
authors: The Methodist hospital, Department of Pathology and Genomic Medicine, Houston, Texas.
authors: Bisong
authors: B
authors: Haupt
authors: Department of Pediatrics, Saint Louis University, St. Louis MO.
authors: Adriana M
authors: AM
authors: Montaño
authors: Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE.
authors: Tsutomu
authors: T
authors: Shimada
authors: Department of Pediatrics, Saint Louis University, St. Louis MO.
authors: William S
authors: WS
authors: Sly
mesh_terms: D000469:Alkaline Phosphatase / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D019902:Chondrocytes / Q000187:drug effects; D003412:Cricetulus; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy / Q000379:methods; D006801:Humans; D007014:Hypophosphatasia / Q000188:drug therapy*; D051379:Mice; D015996:Survival Rate; D025101:Vitamin B 6 / Q000494:pharmacology
chemical_list: D025101:Vitamin B 6; C548267:ALPL protein, human; D000469:Alkaline Phosphatase
references: Mol Genet Metab. 2006 Jul;88(3):244-55
references: 16616566
references: Hum Mol Genet. 2003 May 1;12(9):961-73
references: 12700165
references: Endocr Rev. 1994 Aug;15(4):439-61
references: 7988481
references: Nat Genet. 1995 Sep;11(1):45-51
references: 7550313
references: Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2205-10
references: 11226217
references: J Dent Res. 2011 Apr;90(4):470-6
references: 21212313
references: Pediatr Pulmonol. 2012 Sep;47(9):917-22
references: 22328548
references: Bone. 2011 Aug;49(2):250-6
references: 21458605
references: J Clin Invest. 1988 Apr;81(4):1234-9
references: 3350970
references: J Bone Miner Res. 2007 Sep;22(9):1397-407
references: 17539739
references: Dev Dyn. 1997 Mar;208(3):432-46
references: 9056646
references: J Pathol. 2001 Jan;193(1):125-33
references: 11169525
references: J Pediatr. 1982 Sep;101(3):379-86
references: 7108657
references: N Engl J Med. 2012 Mar 8;366(10):904-13
references: 22397652
references: J Bone Miner Res. 2008 Jun;23(6):777-87
references: 18086009
references: Curr Opin Pediatr. 2007 Dec;19(6):628-35
references: 18025928
references: Bone. 2007 Jun;40(6):1655-61
references: 17395561
references: J Bone Miner Res. 2012 Aug;27(8):1722-34
references: 22461224