Journal of Inherited Metabolic Disease

, Volume 37, Issue 2, pp 309–317

Enzyme replacement therapy on hypophosphatasia mouse model

  • Hirotaka Oikawa
  • Shunji Tomatsu
  • Bisong Haupt
  • Adriana M. Montaño
  • Tsutomu Shimada
  • William S. Sly
Original Article

DOI: 10.1007/s10545-013-9646-7

Cite this article as:
Oikawa, H., Tomatsu, S., Haupt, B. et al. J Inherit Metab Dis (2014) 37: 309. doi:10.1007/s10545-013-9646-7

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.

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

t1/2

apparent elimination half-life

TB

toluidine blue

Tmax

concentration peak time

TNSALP

tissue-nonspecific alkaline phosphatase

Vd

steady-state distribution volume

Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Hirotaka Oikawa
    • 1
  • Shunji Tomatsu
    • 2
  • Bisong Haupt
    • 3
  • Adriana M. Montaño
    • 4
  • Tsutomu Shimada
    • 2
  • William S. Sly
    • 5
  1. 1.Growth, Development and Metabolism ProgramSingapore Institute for Clinical SciencesSingaporeSingapore
  2. 2.Department of Biomedical ResearchNemours/Alfred I. duPont Hospital for ChildrenWilmingtonUSA
  3. 3.Department of Pathology and Genomic MedicineThe Methodist HospitalHoustonUSA
  4. 4.Department of PediatricsSaint Louis UniversitySt. LouisUSA
  5. 5.Department of Molecular BiologySaint Louis UniversitySt. LouisUSA