Hypophosphatasia (HPP) is metabolic disease caused by mutations in the gene encoding tissue non-specific Alkaline Phosphatase (TNAP), and is associated with a loss of TNAP function. Decreased or complete loss of TNAP function affects bone formation and calcification. In its most severe form HPP presents perinatally and is usually lethal within days to weeks after birth due to bone malformation, seizures and failure to thrive. Infantile HPP presents during the first 6 months after birth with bone malformation or rickets, craniosynostosis, hypercalcemia and nephrocalcinosis, and seizures, associated with high first year mortality rate.

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The incidence and prevalence of all forms of HPP are thought to be less than 1:100,000. The European Medicines Agency (EMA) recently granted an orphan designation to recAP for the treatment of HPP.

Pre-clinical developmentrecAP was tested in a knockout (Alpl−/−) mice model for life-threatening HPP. Mice received daily subcutaneous injections of recAP at doses of 1, 8 or 16 mg/kg, from birth for up to 53 days.

It was shown that the administration of recAP improved the manifestations of HPP in these mice. Lifespan and body weight of these mice were normalized, and vitamin B6-associated seizures were absent with recAP. Radiographs, μCT and histological analyses documented improved mineralization in cortical and trabecular bone and secondary ossification centers in long bones of recAP-treated mice. There was no evidence of craniosynostosis in the highest dose of recAP-treated mice and ectopic calcification was not detected by radiography and histology in the aortas, stomachs, kidneys or lungs in any of the treatment groups. Molar tooth development and function improved with the highest recAP dose, including enamel, dentin, and tooth morphology.

Background information on the HPP model and recAP’s study results: Gasque et al, Bone 2015

 


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