ArticleJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research2025
Preclinical evaluation of the efficacy and safety of adeno-associated virus 8-tissue-nonspecific alkaline phosphatase-D10 in Alpl-/- and AlplPrx1/Prx1 mouse models for the treatment of early and late-onset hypophosphatasia.
Article in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed.
- TNAP and PHOSPHO1 Function Synergistically to Afford Critical Control Over the Mineralization of the Postnatal Murine Skeleton.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Effects of comorbid chronic kidney disease on late-onset hypophosphatasia mice under treatment with asfotase alfa.JBMR plus · 2026Article
- ENPP1 inhibition as a therapeutic approach for later-onset hypophosphatasia.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2026Article
- Hypophosphatasia-pathophysiological understanding, preclinical data looking beyond the skeleton, and upcoming treatments.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2026Review
- TNAP and PHOSPHO1 function synergistically to afford critical control over the mineralisation of the postnatal murine skeleton.bioRxiv : the preprint server for biology · 2026Article
- Article
- Review
- Proof-of-principle for enhanced dentoalveolar mineralization using exogenous tissue-nonspecific alkaline phosphatase in theJBMR plus · 2025Article
- Pathophysiology of Femoral Fractures in Hypophosphatasia.Current osteoporosis reports · 2025Review
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Abstract
We previously documented successful resolution of skeletal and dental disease in the infantile and late-onset murine models of hypophosphatasia (HPP) with a single injection of an adeno-associated serotype 8 vector encoding mineral-targeted TNAP (AAV8-TNAP-D10). Here, we conducted dosing studies in both HPP mouse models. A single escalating dose from 4 × 108 up to 4 × 1010 (vg/b) was intramuscularly injected into 4-day-old Alpl-/- mice (an infantile HPP model) and a single dose from 4 × 106 up to 4 × 109 (vg/b) was administered to 8-wk-old AlplPrx1/Prx1 mice (a late-onset HPP model). Wild-type littermates were used as controls. Serum alkaline phosphatase activity was increased, and PPi levels were decreased in a dose-dependent manner in both the Alpl-/- and AlplPrx1/Prx1 models. Radiographic and μCT analysis of long bones of female and male Alpl-/- mice showed full correction of skeletal phenotype at 4 × 1010 vg/b. We observed full correction of the bone phenotype at 4 × 108 and 4 × 109 in female AlplPrx1/Prx1 mice, but bones remained hypomineralized with the 4 × 106 and 4 × 107 (vg/b) doses after 70 d of treatment. We observed skeletal improvements using the 4 × 109 (vg/b) dose, but the phenotype was not fully corrected in male AlplPrx1/Prx1. Immunohistochemistry using anti-TNAP and anti-D10 antibodies showed high immunolocalization in the femurs of female AlplPrx1/Prx1 mice, while D10 immunolocalization was high in the liver of male AlplPrx1/Prx1 mice at a dose of 4 × 109 (vg/b). This sex-dependent difference was not seen in the infantile HPP model. A serum proteome analysis showed enhanced inflammatory pathways in treated AlplPrx1/Prx1 males compared to treated female mice. We also found a few areas of ectopic calcification in soft organs at the highest tested dose of 4 × 1010 (vg/b) in Alpl-/- or 4 × 109 (vg/b) in the AlplPrx1/Prx1 model. This pre-clinical study will inform the design of clinical trials to develop gene therapy in early-onset and late-onset HPP patients.
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