title: Dose response of bone-targeted enzyme replacement for murine hypophosphatasia.
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.
authors: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors: Manisha C
authors: MC
authors: Yadav
authors: Isabelle
authors: I
authors: Lemire
authors: Pierre
authors: P
authors: Leonard
authors: Guy
authors: G
authors: Boileau
authors: Laurent
authors: L
authors: Blond
authors: Martin
authors: M
authors: Beliveau
authors: Esther
authors: E
authors: Cory
authors: Robert L
authors: RL
authors: Sah
authors: Michael P
authors: MP
authors: Whyte
authors: Philippe
authors: P
authors: Crine
authors: José Luis
authors: JL
authors: Millán
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D056947:Enzyme Replacement Therapy / Q000379:methods; D007014:Hypophosphatasia / Q000188:drug therapy*; D051379:Mice; D018345:Mice, Knockout; D010018:Osteomalacia / Q000188:drug therapy; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D011994:Recombinant Proteins; D000469:Alkaline Phosphatase