Enpp1 inhibition: a promising oral therapy for later-onset hypophosphatasia

Hypophosphatasia (HPP) is a rare, inherited metabolic bone disorder characterized by deficient activity of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme encoded by the ALPL gene. Loss-of-function mutations in ALPL lead to reduced TNAP activity, resulting in the accumulation of extracellular inorganic pyrophosphate (PPi), a potent inhibitor of hydroxyapatite crystal formation and skeletal mineralization. Clinically, this presents as a broad spectrum of dento-osseous complications, including premature tooth loss, rickets or osteomalacia, and calcific arthropathies.