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Alkaline Phosphatase Replacement Therapy for Hypophosphatasia in Development and Practice

  • S. A. BowdenEmail author
  • B. L. Foster
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1148)

Abstract

Hypophosphatasia (HPP) is an inherited disorder that affects bone and tooth mineralization characterized by low serum alkaline phosphatase. HPP is caused by loss-of-function mutations in the ALPL gene encoding the protein, tissue-nonspecific alkaline phosphatase (TNSALP). TNSALP is expressed by mineralizing cells of the skeleton and dentition and is associated with the mineralization process. Generalized reduction of activity of the TNSALP leads to accumulation of its substrates, including inorganic pyrophosphate (PPi) that inhibits physiological mineralization. This leads to defective skeletal mineralization, with manifestations including rickets, osteomalacia, fractures, and bone pain, all of which can result in multi-systemic complications with significant morbidity, as well as mortality in severe cases. Dental manifestations are nearly universal among affected individuals and feature most prominently premature loss of deciduous teeth. Management of HPP has been limited to supportive care until the introduction of a TNSALP enzyme replacement therapy (ERT), asfotase alfa (AA). AA ERT has proven to be transformative, improving survival in severely affected infants and increasing overall quality of life in children and adults with HPP. This chapter provides an overview of TNSALP expression and functions, summarizes HPP clinical types and pathologies, discusses early attempts at therapies for HPP, summarizes development of HPP mouse models, reviews design and validation of AA ERT, and provides up-to-date accounts of AA ERT efficacy in clinical trials and case reports, including therapeutic response, adverse effects, limitations, and potential future directions in therapy.

Keywords

Hypophosphatasia Alkaline phosphatase Asfotase alfa Bone mineralization Rickets Osteomalacia Teeth 

Abbreviations

HPP

Hypophosphatasia

ALPL

Alkaline phosphatase gene

TNSALP

Tissue-nonspecific isoenzyme of alkaline phosphatase

ALP

Alkaline phosphatase enzyme activity, circulating

IAP

Intestinal alkaline phosphatase protein

ALPI

Intestinal alkaline phosphatase gene

PLAP

Placental alkaline phosphatase protein

ALPP

Placental alkaline phosphatase gene

GCAP

Germ cell alkaline phosphatase protein

ALPPL2

Germ cell alkaline phosphatase gene

AA

Asfotase alfa

ERT

Enzyme replacement therapy

Pi

Inorganic phosphate

PPi

Inorganic pyrophosphate

PLP

Pyridoxal 5′-phosphate

PEA

Phosphoethanolamine

GPI

Glycosylphosphatidylinositol

HAP

Hydroxyapatite

CHO

Chinese hamster ovary cells

BSP

Bone sialoprotein

OPN

Osteopontin

DSP

Dentin sialoprotein

PHEX

Phosphate-regulating endopeptidase

XLH

X-linked hypophosphatemia

PDB

Paget’s disease of the bone

PDL

Periodontal ligament

OMIM

Online Mendelian Inheritance in Man compendium

ANK/ANKH

Progressive ankylosis protein

ENPP1

Ectonucleotide pyrophosphatase phosphodiesterase 1 protein

PTH

Parathyroid hormone

TPTD

Teriparatide

BMT

Bone marrow transplantation

SCB

Stromal cell boost

IV

Intravenous

SC

Subcutaneous

IP

Intraperitoneal

Notes

Acknowledgments

We thank the subjects and their families for their cooperation and assistance with this research. This research was supported by research grants from Soft Bones, Inc. to BLF and grant AR 066110 to BLF from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). We thank Dr. Jose Luis Millán for providing images for reproduction. We thank Mr. Michael B. Chavez for adaptation of the TNSALP 2D model in Fig. 13.2m. For more information on hypophosphatasia for affected individuals, researchers, or health care professionals, see the Soft Bones, Inc. website at https://www.softbones.org/.

Conflict of Interest

BLF has served as a consultant and speaker for Alexion Pharmaceuticals, Inc., and received two research grants from Soft Bones, Inc., a nonprofit patient advocacy, support, and education group for families with hypophosphatsia. The authors report no other conflicts of interest in this work.

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Division of Endocrinology, Department of PediatricsNationwide Children’s Hospital/The Ohio State University College of MedicineColumbusUSA
  2. 2.Division of Biosciences, College of DentistryThe Ohio State UniversityColumbusUSA

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