Figure 4.

Asfotase alfa enzyme replacement therapy in a mouse model of HPP.

Notes: (A) Model of recombinant asfotase alfa enzyme showing tissue-non-specific alkaline phosphatase (TNSALP) dimer (blue), human IgG₁ Fc domain (green), and D₁₀ deca-aspartate tail (red). On the right, a simulated model shows predicted interaction of the highly negatively charged D₁₀ tail with the positively charged calcium plane in hydroxyapatite (HAP) crystal. (B) Percent survival of wild-type (WT), untreated Alpl^−/−, and Alpl^−/− mice receiving 8.2 mg/kg asfotase alfa enzyme replacement therapy (ERT) over the course of the study. (C) Radiographs of hind limbs at 16 days postnatal (dpn) shows improvements in long bone lengths, shape, and appearance of secondary ossification centers in Alpl^−/− mice receiving ERT. (D) Micro-computed tomography (micro-CT) of skulls at 15 dpn shows that ERT produces improvements in size, shape, and mineralization of craniofacial bones in Alpl^−/− mice. (E) Von Kossa stained undecalcified tissue sections (left panels for each group) indicate that ERT rescues root dentin mineralization in Alpl^−/− mice, as indicated by black stained appearance of mineralized tissues. H&E-stained sections (right panels for each group) reveal that ERT prevents acellular cementum (AC) hypoplasia (*) in Alpl^−/− mouse molars, allowing periodontal ligament (PDL) attachment and normal periodontal architecture. Images in panel A are reproduced with permission (via republication of material within the agreed-upon thresholds between STM Permissions Guidelines signatories) from McKee et al.81 Graph in panel B, images in panel C, and von Kossa images in panel E are reproduced with permission from Copyright © 2008 ASBMR. Millán JL, Narisawa S, Lemire I, et al. Enzyme replacement therapy for murine hypophosphatasia. J Bone Miner Res. 2008;23(6):777–787.76 Images in panel D are reprinted with permission from Bone, Volume 78, Liu J, Campbell C, Nam HK, et al, Enzyme replacement for craniofacial skeletal defects and craniosynostosis in murine hypophosphatasia, Pages 203–211, Copyright (2015) with permission from Elsevier.80 H&E images in panel E are previously unpublished data from BLF.