{"doi":"10.1093/jbmr/zjaf005","title":"Preclinical evaluation of the efficacy and safety of adeno-associated virus 8-tissue-nonspecific alkaline phosphatase-D10 in <i>Alpl-/-</i> and <i>AlplPrx1/Prx1</i> mouse models for the treatment of early and late-onset hypophosphatasia","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.","journal":"Journal of Bone and Mineral Research","year":2025,"id":516327,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1381676,"name":"Cíntia Kazuko Tokuhara","orcid":"0000-0002-1852-5986","position":1,"is_corresponding":false},{"id":815405,"name":"Fatma F. Mohamed","orcid":"0000-0003-1008-6541","position":2,"is_corresponding":false},{"id":386503,"name":"Sonoko Narisawa","orcid":null,"position":3,"is_corresponding":false},{"id":1370762,"name":"Elis Janaína Lira dos Santos","orcid":"0000-0002-0324-3863","position":4,"is_corresponding":false},{"id":932295,"name":"Natalie L. Andras","orcid":null,"position":5,"is_corresponding":false},{"id":1382147,"name":"Mohammad Shadid","orcid":null,"position":6,"is_corresponding":false},{"id":777794,"name":"Koichi Miyake","orcid":null,"position":7,"is_corresponding":false},{"id":365098,"name":"Brian L. Foster","orcid":"0000-0003-3444-0576","position":8,"is_corresponding":false},{"id":385334,"name":"José Luís Millán","orcid":"0000-0002-1547-2671","position":9,"is_corresponding":false},{"id":385332,"name":"Flávia Amadeu de Oliveira","orcid":"0000-0003-3063-6694","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:48:49.486328Z","pmid":"39799564","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}