BONE-TARGETED ALKALINE PHOSPHATASE - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 418

FIGURE 28.2 Left panels: Targeting TNAP to mineral restores bone and tooth mineralization defects
seen in TNAP-deficient (Akp2 / ) mice, as assessed by microcomputed tomography. Coronal views of
mandibles from 16-day-old mice (vehicle-injected Akp2 / , ENB-0040-treated Akp2 / , and wild-type
[WT]) as a single X-ray slice (images on the left), or as reconstructions of multiple slices (images on the
right). (A) Vehicle-injected Akp2 / mice show extensive regions of unmineralized root (and root
analog) dentin (asterisks), as well as surrounding hypomineralized alveolar bone. (B) ENB-0040-treated
Akp2 / mice show complete mineralization of all incisor and molar tooth tissues and alveolar bone,
which are indistinguishable from WT tissues (C). Arrows indicate mineralized dentin and acellular
cementum combined defects. Right panels: Presence of acellular cementum in ENB-0040-treated
Akp2 / mice visualized by histology and immunohistochemistry with anti-osteopontin antibodies.
(A-C) Plastic coronal sections of the first molar near the cemento-enamel junction, showing acellular
cementum along the root surface in ENB-0040-treated Akp2 / mice. Tissues appear comparable to
those seen inWT mice (arrows and insets). This acellular cementum layer is absent (asterisks) in vehicle-
injected Akp2 / mice. Rectangles 1 and 2 in (a) indicate sites adjacent to mineralized (Min.) and
unmineralized (UnMin.) dentin, respectively. Unmineralized dentin is commonly seen in TNAP-
deficient mice. Electron micrographs of boxed areas 1 and 2 are shown in Fig. 4. (D-F) Immuno-
histochemical localization of osteopontin (red, arrows, and inset), as a marker of acellular cementum,
confirms histologic observations in corresponding panels a-c showing acellular cementum following
ENB-0040 treatment (Akp2 / -treated) but absence of a discrete immunostained layer (asterisk in inset)
in vehicle-treated Akp2 / mice. PDL, periodontal ligament; En-S, enamel space after decalcification.
Magnification bars equal 100 m m. OPN, osteopontin. Source: The final definitive version of this figure
has been published in Journal of Dental Research, Reference 24. 90(4): 470-476, January 2011, by
SAGE publication, Inc, All rights reserved # .

scientific meetings, but appear to indicate remarkable
improvement of the skeletal condition in HPP infants and
children treated with ENB-0040 [37-46].

restriction of dietary calcium or administration of calciu-
retics, or patients with craniosynostosis may need surgical
intervention. Likewise, fractures are treated by prolonged
casting or stabilization with orthopedic hardware, and dental
hygiene is carefully monitored in individuals with dental
manifestations of the disease. Earlier attempts at more
definitive HPP treatment have met with limited success.
Use of a bisphosphonate (a synthetic analog of pyro-
phosphate) in one infant reportedly had no discernible effect
on the skeleton, and the infant experienced progressive

28.5 ALTERNATIVES/VARIANTS
OF THIS APPROACH

To date, HPP treatment has been essentially symptomatic
[3]. For example, infants with hypercalcemia may require