Altered mitochondrial bioenergetics in hypophosphatasia and the influence of efzimfotase alfa

Introduction: Hypophosphatasia (HPP) is a rare inherited metabolic disease caused by deficient tissue-nonspecific alkaline phosphatase (ALP) activity. HPP is characterized by skeletal and nonskeletal symptoms, including muscle weakness, although the etiology of nonskeletal manifestations is poorly understood.We hypothesized that mitochondrial dysfunction is present in muscle tissue in HPP, independent of skeletal manifestations, and that the investigational ALP enzyme replacement therapy efzimfotase alfa improves mitochondrial bioenergetics. Methods : Body weight, bone mineralization, and survival were validated in Akp2GW-/- mice against Akp2-/- mice, an established model of HPP. To assess mitochondrial bioenergetics, spare respiratory capacity was measured in skeletal muscle fiber bundles in age- and sex-matched Akp2GW-/- and Akp2GW+/+ (wild-type [WT]) mice. In addition to the bioenergetics study, cellular ultrastructure was assessed using transmission electron microscopy of muscle biopsies from 3 people with HPP to corroborate evidence of altered mitochondrial bioenergetics found in Akp2GW-/- mice. Results : No significant differences were found between Akp2-/- and Akp2GW-/- mice for any outcomes assessed, confirming Akp2GW-/- mice as a valid model of HPP. Mean mitochondrial spare respiratory capacity in vehicle-treated Akp2GW-/- mice was 30% of WT mice and was reduced independent of skeletal manifestations. Efzimfotase alfa treatment significantly improved spare respiratory capacity in muscle fiber bundles from Akp2GW-/- mice by 257% relative to vehicle (P=0.0008), increasing spare respiratory capacity to 107% of tissue from WT mice. The cellular ultrastructure of biopsies from patients with HPP showed atypical mitochondrial morphology, including branching cristae and dispersed matrix, suggesting impaired function. Discussion: Altered mitochondrial bioenergetics may be a mechanism of muscle weakness in patients with HPP. The investigational therapy efzimfotase alfa (currently in phase 3 clinical trials) has the potential to benefit patients with muscle weakness.