Dose response of bone-targeted enzyme replacement for murine hypophosphatasia

Manisha C. Yadav, Isabelle Lemire, Pierre Leonard, Guy Boileau, Laurent Blond, Martin Beliveau, Esther Cory, Robert L. Sah, Michael P. Whyte, Philippe Crine, José Luis Millán

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40 Scopus citations

Abstract

Hypophosphatasia (HPP) features rickets or osteomalacia from tissue-nonspecific alkaline phosphatase (TNSALP) deficiency due to deactivating mutations within the ALPL gene. Enzyme replacement therapy with a bone-targeted, recombinant TNSALP (sALP-FcD 10, renamed ENB-0040) prevents manifestations of HPP when initiated at birth in TNSALP knockout (Akp2 -/-) mice. Here, we evaluated the dose-response relationship of ENB-0040 to various phenotypic traits of Akp2 -/- mice receiving daily subcutaneous (SC) injections of ENB-0040 from birth at 0.5, 2.0, or 8.2mg/kg for 43days. Radiographs, μCT, and histomorphometric analyses documented better bone mineralization with increasing doses of ENB-0040. We found a clear, positive correlation between ENB-0040 dose and prevention of mineralization defects of the feet, rib cage, lower limbs, and jaw bones. According to a dose-response model, the ED 80 (the dose that prevents bone defects in 80% of mice) was 3.2, 2.8 and 2.9mg/kg/day for these sites, respectively. Long bones seemed to respond to lower daily doses of ENB-0040. There was also a positive relationship between ENB-0040 dose and survival. Median survival, body weight, and bone length all improved with increasing doses of ENB-0040. Urinary PP i concentrations remained elevated in all treatment groups, indicating that while this parameter is a good biochemical marker for diagnosing HPP in patients, it may not be a good follow up marker for evaluating response to treatment when administering bone-targeted TNSALP to mice. These dose-response relationships strongly support the pharmacological efficacy of ENB-0040 for HPP, and provide the experimental basis for the therapeutic range of ENB-0040 chosen for clinical trials.

Original languageEnglish
Pages (from-to)250-256
Number of pages7
JournalBone
Volume49
Issue number2
DOIs
StatePublished - Aug 1 2011

Keywords

  • Alkaline phosphatase
  • Calcification
  • ENB-0040
  • Osteomalacia
  • Rickets

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    Yadav, M. C., Lemire, I., Leonard, P., Boileau, G., Blond, L., Beliveau, M., Cory, E., Sah, R. L., Whyte, M. P., Crine, P., & Millán, J. L. (2011). Dose response of bone-targeted enzyme replacement for murine hypophosphatasia. Bone, 49(2), 250-256. https://doi.org/10.1016/j.bone.2011.03.770