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: Hirotaka Oikawa, Shunji Tomatsu, Bisong Haupt, Adriana M Montaño, Tsutomu Shimada, William S Sly
• Journal: Journal of inherited metabolic disease (J Inherit Metab Dis) Vol. 37 Issue 2 Pg. 309-317 (Mar 2014) ISSN: 1573-2665 [Electronic] United States
• PMID: 23978959 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Vitamin B 6
• ALPL protein, human
• Alkaline Phosphatase

Topics

• Alkaline Phosphatase (pharmacology)
• Animals
• CHO Cells
• Chondrocytes (drug effects)
• Cricetulus
• Disease Models, Animal
• Enzyme Replacement Therapy (methods)
• Humans
• Hypophosphatasia (drug therapy)
• Mice
• Survival Rate
• Vitamin B 6 (pharmacology)