Hypophosphatasia - Pathophysiological understanding, preclinical data looking beyond the skeleton, and upcoming treatments.

Abstract

Hypophosphatasia (HPP) is the genetic disorder caused by loss-of-function mutations in the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP), an enzyme essential for physiological skeletal/dental mineralization. In HPP, TNAP deficiency leads to the accumulation of extracellular pyrophosphate (PPi), a potent inhibitor of calcification, resulting in skeletal and dental hypomineralization, with disease severity varying from the life-threatening perinatal and infantile forms to the milder later-onset forms that manifest in adulthood or only affect dentition. Enzyme replacement therapy based on recombinant mineral-targeted alkaline phosphatase (asfotase alfa) has been approved multinationally since 2015 for the treatment of pediatric-onset HPP, remarkably increasing the lifespan, their skeletal condition and the quality of life of patients affected by the severe forms of HPP. However, non-skeletal symptoms remain as important clinical concerns. As its moniker implies, TNAP is expressed in a large variety of tissues and cell types, and TNAP may be engaged in distinct metabolic pathways in each tissue. A better understanding of the cells expressing TNAP physiologically, the metabolic pathways involved and the natural substrates of TNAP in each tissue will help design improved and/or alternative therapies to prevent/correct known or yet to be discovered non-skeletal manifestations of HPP. Figure 1 graphically lays out the topics discussed in this invited perspective article that follows the contents of the Louis V Avioli Memorial lecture delivered during the ASBMR 2025 annual meeting.