Efzimfotase Alfa Improves Respiratory Capacity in Muscle Tissue From a Mouse Model of <scp>HPP</scp>

Hypophosphatasia (HPP) is an inherited metabolic disease caused by deficient tissue-nonspecific alkaline phosphatase (ALP) activity and characterized by skeletal and nonskeletal symptoms, including muscle weakness and fatigue. We hypothesized that mitochondrial respiration is impaired in muscle in HPP, independent of skeletal manifestations, and that the second-generation ALP enzyme replacement therapy (ERT) efzimfotase alfa improves respiration. Akp2GW^-/- mice were used for this purpose. Body weight, bone mineralization, and survival were validated in Akp2GW^-/- mice versus Akp2^-/- mice, an established model of HPP. No significant differences were found, validating the Akp2GW^-/- model. Respiratory outcomes were measured in skeletal muscle fiber bundles in age- and sex-matched Akp2GW^-/- and Akp2GW^+/+ (wild-type) mice; bone mineralization was assessed. Mean maximal respiration and mitochondrial spare respiratory capacity (SRC) in vehicle-treated Akp2GW^-/- mice were 37% and 30% of values from wild-type mice, respectively, independent of skeletal manifestations. Efzimfotase alfa treatment significantly improved maximal respiration in tissue from Akp2GW^-/- mice by 147% versus vehicle (<i>p</i> = 0.0059) and improved SRC by 262% versus vehicle (<i>p</i> = 0.0008). Mean maximal respiration and SRC in tissue from efzimfotase alfa-treated Akp2GW^-/- mice were 92% and 107%, respectively, of tissue from wild-type mice. Cellular ultrastructure of muscle biopsies from people with HPP showed atypical mitochondrial morphology, including branching cristae and dispersed matrix. In a mouse model of HPP, we show that the altered mitochondrial respiration in skeletal muscle is improved by ERT and that HPP is characterized by altered muscle mitochondrial morphology in humans. Together, these data suggest ERT could improve muscular symptoms in HPP.