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.
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Abbreviations
- ALP:
-
alkaline phosphatase
- AUC:
-
areas under the curve
- BMD:
-
bone mineral density
- CL:
-
total clearance
- Cmax:
-
peak concentration
- D10:
-
a deca-aspartate sequence
- ERT:
-
enzyme replacement therapy
- HE:
-
hematoxylin and eosin
- HPP:
-
hypophosphatasia
- IV:
-
intravenously
- LSDs:
-
lysosomal storage disorders
- MPS:
-
mucopolysaccharidosis
- MRT:
-
mean residence time
- PLP:
-
pyridoxal 5-phosphate
- pNPP:
-
p-nitrophenyl phosphate
- PPi:
-
inorganic pyrophosphate
- SC:
-
subcutaneously
- t 1/2 :
-
apparent elimination half-life
- TB:
-
toluidine blue
- Tmax:
-
concentration peak time
- TNSALP:
-
tissue-nonspecific alkaline phosphatase
- Vd:
-
steady-state distribution volume
References
Baumgartner-Sigl S, Haberlandt E, Mumm S et al (2007) Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissuenonspecific alkaline phosphatase gene. Bone 40:1655–61
Burrow TA, Hopkin RJ, Leslie ND, Tinkle BT, Grabowski GA (2007) Enzyme reconstitution/replacement therapy for lysosomal storage diseases. Curr Opin Pediatr 19:628–35
Hough TA, Polewski M, Johnson K et al (2007) Novel mouse model of autosomal semidominant adult hypophosphatasia has a splice site mutation in the tissue nonspecific alkaline phosphatase gene Akp2. J Bone Miner Res 22:1397–407
MacGregor GR, Zambrowicz BP, Soriano P (1995) Tissue non-specific alkaline phosphatase is expressed in both embryonic and extraembryonic lineages during mouse embryogenesis but is not requires for migration of primordial germ cells. Development 121(5):1487–96
McKee MD, Nakano Y, Masica DL et al (2011) Enzyme replacement therapy prevents dental defects in a model of hypophosphatasia. J Dent Res 90:470–6
Millán JL, Narisawa S, Lemire I et al (2008) Enzyme replacement therapy for murine hypophosphatasia. J Bone Miner Res 23:777–87
Narisawa S, Fröhlander N, Millán JL (1997) Inactivation of two mouse alkaline phosphatase genes and establishment of a model of infantile hypophosphatasia. Dev Dyn 208:432–46
Narisawa S, Wennberg C, Millán JL (2001) Abnormal vitamin B6 metabolism in alkaline phosphatase knockout mice causes multiple abnormalities, but not the impaired bone mineralization. J Pathol 193:125–33
Nishioka T, Tomatsu S, Gutierrez MA et al (2006) Enhancement of drug delivery to bone: Characterization of human tissue-nonspecific alkaline phosphatase tagged with an acidic oligopeptide. Mol Genet Metab 88:244–55
Rodriguez E, Bober MB, Davey L et al (2012) Respiratory mechanics in an infant with perinatal lethal hypophosphatasia treated with human recombinant enzyme replacement therapy. Pediatr Pulmonol 47:917–22
Sly WS, Vogler C, Grubb JH et al (2001) Active site mutant transgene confers tolerance to human beta-glucuronidase without affecting the phenotype of MPS VII mice. Proc Natl Acad Sci U S A 98:2205–10
Tomatsu S, Orii KO, Vogler C et al (2003) Production of MPS VII mouse (Gus(tm(hE540A x mE536A)Sly)) doubly tolerant to human and mouse beta-glucuronidase. Hum Mol Genet 12:961–73
Waymire KG, Mahuren JD, Jaje JM, Guilarte TR, Coburn SP, MacGregor GR (1995) Mice lacking tissue non-specific alkaline phosphatase die from seizures due to defective metabolism of vitamin B-6. Nat Genet 11:45–51
Whyte MP (1994) Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocr Rev 15:439–61
Whyte MP (2001) Hypophosphatasia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW (eds) The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York, pp 5313–29
Whyte MP, Valdes R Jr, Ryan LM, McAlister WH (1982) Infantile hypophosphatasia: Enzyme replacement therapy by intravenous infusion of alkaline phosphatase-rich plasma from patients with Paget bone disease. J Pediatr 101:379–86
Whyte MP, Mahuren JD, Fedde KN, Cole FS, McCabe ER, Coburn SP (1988) Perinatal hypophosphatasia: tissue levels of vitamin B6 are unremarkable despite markedly increased circulating concentrations of pyridoxal-5'-phosphate. Evidence for an ectoenzyme role for tissue-nonspecific alkaline phosphatase. J Clin Invest 81:1234–9
Whyte MP, Greenberg CR, Salman NJ et al (2012) Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med 366:904–13
Yadav MC, Lemire I, Leonard P et al (2011) Dose response of bone-targeted enzyme replacement for murine hypophosphatasia. Bone 49:250–6
Yadav MC, de Oliveira RC, Foster BL et al (2012) Enzyme replacement prevents enamel defects in hypophosphatasia mice. J Bone Miner Res 27:1722–34
Acknowledgments
This work was supported by grants from the Austrian MPS Society, and International Morquio Organization (Carol Ann Foundation). S.T. is supported by National Institutes of Health grant 8P20 GM103464-08. The content of the article has not been influenced by the sponsors.
Dr. Tomatsu, a principal investigator, was the former employee of Saint Louis University, while the experiments of the project were conducted and completed.
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Communicated by: Maurizio Scarpa
Hirotaka Oikawa, Shunji Tomatsu and Bisong Haupt contributed equally to this manuscript and agreed to share the first co-authors.
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Oikawa, H., Tomatsu, S., Haupt, B. et al. Enzyme replacement therapy on hypophosphatasia mouse model. J Inherit Metab Dis 37, 309–317 (2014). https://doi.org/10.1007/s10545-013-9646-7
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DOI: https://doi.org/10.1007/s10545-013-9646-7