Alkaline Phosphatase Replacement Therapy for Hypophosphatasia in Development and Practice

Bowden, Sasigarn A; Foster, Brian L.

doi:10.1007/978-981-13-7709-9_13

Cited by 18 publications

(38 citation statements)

References 180 publications

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“…Extensive literature supports the concept that development and function of periodontal tissues are affected by perturbations in P i /PP i metabolism. Inactivating mutations in ALPL cause reduced TNAP function, decreased circulating ALP, and increased PP i levels in the inherited disorder HPP (OMIM#241500, 241510, 146300; Whyte 2016; Bowden and Foster 2019). Dental defects, including acellular cementum hypoplasia, periodontal disease, and premature loss of primary and secondary dentition, are common among individuals with HPP.…”

Section: Discussionmentioning

confidence: 99%

“…Enzyme replacement therapy with mineral-targeted TNAP-D 10 has been effective at correcting prolonging the life span and normalizing skeletal and dental mineralization in HPP mouse models (Millan et al 2008; McKee et al 2011; Foster et al 2012; Whyte 2016). Enzyme replacement therapy has been effective as a first-in-class treatment for patients with HPP, though data analyzing therapeutic effects on dentoalveolar tissues are lacking (Bowden and Foster 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Tissue-nonspecific alkaline phosphatase (gene: Alpl , mouse; ALPL , human; protein: TNAP) promotes mineralization by hydrolyzing PP i to produce P i (Millan 2006). TNAP is expressed by mineralizing cells, including cementoblasts and osteoblasts, and loss-of-function mutations result in increased PP i levels and the inherited hypomineralization disorder hypophosphatasia (HPP; OMIM#241500, 241510, 146300), which features tooth loss due to cementum defects (Bowden and Foster 2019). The progressive ankylosis protein ( Ank /ANK in mouse, ANKH /ANK in human) is a transmembrane regulator of PP i transport to the extracellular space (Ho et al 2000; Szeri et al 2020).…”

Section: Introductionmentioning

confidence: 99%

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Delivery of Alkaline Phosphatase Promotes Periodontal Regeneration in Mice

Nagasaki

Kear

et al. 2021

J Dent Res

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Factors regulating the ratio of pyrophosphate (PPi) to phosphate (Pi) modulate biomineralization. Tissue-nonspecific alkaline phosphatase (TNAP) is a key promineralization enzyme that hydrolyzes the potent mineralization inhibitor PPi. The goal of this study was to determine whether TNAP could promote periodontal regeneration in bone sialoprotein knockout mice ( Ibsp−/− mice), which are known to have a periodontal disease phenotype. Delivery of TNAP was accomplished either systemically (through a lentiviral construct expressing a mineral-targeted TNAP-D10 protein) or locally (through addition of recombinant human TNAP to a fenestration defect model). Systemic TNAP-D10 delivered by intramuscular injection at 5 d postnatal (dpn) increased circulating alkaline phosphatase (ALP) levels in Ibsp−/− mice by 5-fold at 30 dpn, with levels returning to normal by 60 dpn when tissues were evaluated by micro–computed tomography and histology. Local delivery of recombinant human TNAP to fenestration defects in 5-wk-old wild type (WT) and Ibsp−/− mice did not alter long-term circulating ALP levels, and tissues were evaluated by micro–computed tomography and histology at postoperative day 45. Systemic and local delivery of TNAP significantly increased alveolar bone volume (20% and 37%, respectively) and cementum thickness (3- and 42-fold) in Ibsp−/− mice, with evidence for periodontal ligament attachment and bone/cementum marker localization. Local delivery significantly increased regenerated cementum and bone in WT mice. Addition of 100-μg/mL bovine intestinal ALP to culture media to increase ALP in vitro increased media Pi concentration, mineralization, and Spp1 and Dmp1 marker gene expression in WT and Ibsp−/− OCCM.30 cementoblasts. Use of phosphonoformic acid, a nonspecific inhibitor of sodium Pi cotransport, indicated that effects of bovine intestinal ALP on mineralization and marker gene expression were in part through Pi transport. These findings show for the first time through multiple in vivo and in vitro approaches that pharmacologic modulation of Pi/PPi metabolism can overcome periodontal breakdown and accomplish regeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Delivery of Alkaline Phosphatase Promotes Periodontal Regeneration in Mice

Nagasaki

Kear

et al. 2021

J Dent Res

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“…ERT using asfotase alfa was shown to be very effective at correcting skeletal and dentoalveolar defects in Alpl −/− mice, with these translational studies leading to its approval in 2015 for treatment of patients with perinatal/infantile‐ and juvenile‐onset HPP, except in Japan, where asfotase alfa is approved for all ages. ( 25 ) However, asfotase alfa ERT requires multiple injections per week, is associated with injection site reactions, and is expensive, ( 27 , 28 ) prompting additional preclinical studies of alternative strategies for HPP treatment. Daily subcutaneous injection of a soluble, non‐mineral‐targeting, recombinant chimeric alkaline phosphatase (ChimAP) prevented seizures, increased survival, but only partially improved the skeletal and dentoalveolar phenotypes in Alpl −/− mice.…”

Section: Discussionmentioning

confidence: 99%

“…Asfotase alfa saved lives of severe neonatal and infantile HPP and improved bone mineralization, motor function, and quality of life in adult HPP. ( 8 , 22 , 23 , 24 , 25 , 26 ) At the same time, the patient burden of multiple injections per week to maintain the efficacy of asfotase alfa and the associated medical cost ( 27 , 28 ) have prompted preclinical studies of alternative strategies for treating HPP.…”

Section: Introductionmentioning

confidence: 99%

Gene Therapy Using Adeno-Associated Virus Serotype 8 Encoding TNAP-D10 Improves the Skeletal and Dentoalveolar Phenotypes in Alpl−/− Mice

Kinoshita

Mohamed

Oliveira

et al. 2020

Journal of Bone and Mineral Research

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Hypophosphatasia (HPP) is caused by loss-of-function mutations in the ALPL gene that encodes tissue-nonspecific alkaline phosphatase (TNAP), whose deficiency results in the accumulation of extracellular inorganic pyrophosphate (PP i ), a potent mineralization inhibitor. Skeletal and dental hypomineralization characterizes HPP, with disease severity varying from life-threatening perinatal or infantile forms to milder forms that manifest in adulthood or only affect the dentition. Enzyme replacement therapy (ERT) using mineral-targeted recombinant TNAP (Strensiq/asfotase alfa) markedly improves the life span, skeletal phenotype, motor function, and quality of life of patients with HPP, though limitations of ERT include frequent injections due to a short elimination half-life of 2.28 days and injection site reactions. We tested the efficacy of a single intramuscular administration of adeno-associated virus 8 (AAV8) encoding TNAP-D 10 to increase the life span and improve the skeletal and dentoalveolar phenotypes in TNAP knockout (Alpl À/À ) mice, a murine model for severe infantile HPP. Alpl À/À mice received 3 Â 10 11 vector genomes/body of AAV8-TNAP-D 10 within 5 days postnatal (dpn). AAV8-TNAP-D 10 elevated serum ALP activity and suppressed plasma PP i . Treatment extended life span of Alpl À/À mice, and no ectopic calcifications were observed in the kidneys, aorta, coronary arteries, or brain in the 70 dpn observational window. Treated Alpl À/À mice did not show signs of rickets, including bowing of long bones, enlargement of epiphyses, or fractures. Bone microstructure of treated Alpl À/À mice was similar to wild type, with a few persistent small cortical and trabecular defects. Histology showed no measurable osteoid accumulation but reduced bone volume fraction in treated Alpl À/À mice versus controls. Treated Alpl À/À mice featured normal molar and incisor dentoalveolar tissues, with the exceptions of slightly reduced molar enamel and alveolar bone density. Histology showed the presence of cementum and normal periodontal ligament attachment. These results support gene therapy as a promising alternative to ERT for the treatment of HPP.

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Young woman with hypophosphatasia: A case report

Siami

Parsamanesh

Kivi

2022

Clinical Case Reports

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Hypophosphatasia is a rare inherited disease defined by teeth and bone mineralization impairment leading to depletion of tissue non‐specific alkaline phosphatase. We define a young woman diagnosed with hypophosphatasia (after several times alkaline phosphatase levels were low) was discovered following femoral fracture. A 30‐year‐old woman who presented for a history of early permanent teeth loss during the last 5 years and HPP‐like symptoms in family history and bone radiograph verified bowing, deficient mineralization, and symmetrical subtrochanteric stress fractures of femurs was referred to our clinic for further management. Blood test findings defined raised phosphorus levels on two occasions at 6.2 and 5.7 mg/dl and insufficient 25‐hydroxy vitamin D level. HPP early diagnosis and adequate treatment, depending on the clinical symptoms along with laboratory tests, could be effective in decreasing the suffering of the disease and side effects.

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Alkaline Phosphatase Replacement Therapy for Hypophosphatasia in Development and Practice

Cited by 18 publications

References 180 publications

Delivery of Alkaline Phosphatase Promotes Periodontal Regeneration in Mice

Delivery of Alkaline Phosphatase Promotes Periodontal Regeneration in Mice

Gene Therapy Using Adeno-Associated Virus Serotype 8 Encoding TNAP-D10 Improves the Skeletal and Dentoalveolar Phenotypes in Alpl−/− Mice

Young woman with hypophosphatasia: A case report

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