Improvement of the skeletal and dental hypophosphatasia phenotype in Alpl-/- mice by administration of soluble (non-targeted) chimeric alkaline phosphatase.

摘要: Abstract Hypophosphatasia (HPP) results from ALPL gene mutations, which lead to a deficiency of tissue-nonspecific alkaline phosphatase (TNAP), and accumulation inorganic pyrophosphate, potent inhibitor mineralization that is also natural substrate TNAP, in the extracellular space. HPP causes disorders including soft bones (rickets or osteomalacia) defects teeth periodontal tissues. Enzyme replacement therapy using mineral-targeting recombinant TNAP has proven effective preventing skeletal dental knockout ( Alpl −/− ) mice, model for life-threatening HPP. Here, we show administration soluble, intestinal-like chimeric (ChimAP) improves manifestations mice. Mice received daily subcutaneous injections ChimAP at doses 1, 8 16 mg/kg, birth up 53 days. Lifespan body weight mice were normalized, vitamin B6-associated seizures absent with 16 mg/kg/day ChimAP. Radiographs, μCT histological analyses documented improved cortical trabecular bone secondary ossification centers long ChimAP16-treated There was no evidence craniosynostosis did not detect ectopic calcification by radiography histology aortas, stomachs, kidneys lungs any treatment groups. Molar tooth development function highest dose, enamel, dentin, morphology. Cementum remained deficient alveolar reduced compared controls, though ChimAP-treated featured attachment retained teeth. This study provides first pharmacological efficacy use