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PHOSPHO1 deficiency leads to early\u2010onset scoliosis, osteomalacia, and fractures that mimic pseudo\u2010HPP. Asfotase alfa, a life\u2010saving enzyme replacement therapy approved for pediatric\u2010onset HPP, requires subcutaneous injections 3 to 6\u00a0times per week. We recently showed that a single injection of an adeno\u2010associated virus vector serotype 8 harboring TNAP\u2010D<jats:sub>10<\/jats:sub> (AAV8\u2010TNAP\u2010D<jats:sub>10<\/jats:sub>) effectively prevented skeletal disease and prolonged life in <jats:italic>Alpl<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice phenocopying infantile HPP. Here, we aimed to determine the efficacy of AAV8\u2010TNAP\u2010D<jats:sub>10<\/jats:sub> in improving the skeletal and dental phenotype in the <jats:italic>Alpl<\/jats:italic><jats:sup><jats:italic>Prx1\/Prx1<\/jats:italic><\/jats:sup> and <jats:italic>Phospho1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mouse models of late\u2010onset (adult) HPP and pseudo\u2010HPP, respectively. A single dose of 3\u2009\u00d7\u200910<jats:sup>11<\/jats:sup> vector genomes per body (vg\/b) was injected intramuscularly into 8\u2010week\u2010old <jats:italic>Alpl<\/jats:italic><jats:sup><jats:italic>Prx1\/Prx1<\/jats:italic><\/jats:sup> and wild\u2010type (WT) littermates, or into 3\u2010day\u2010old <jats:italic>Phospho1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> and WT mice, and treatment efficacy was evaluated after 60\u2009days for late\u2010onset HPP mice and after 90\u2009days for <jats:italic>Phospho1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. Biochemical analysis showed sustained serum alkaline phosphatase activity and reduced plasma PP<jats:sub>i<\/jats:sub> levels, and radiographic images, micro\u2010computed tomography (micro\u2010CT) analysis, and hematoxylin and eosin (H&amp;E) staining showed improvements in the long bones in the late\u2010onset HPP mice and corrected scoliosis in the <jats:italic>Phospho1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Micro\u2010CT analysis of the dentoalveolar complex did not reveal significant changes in the phenotype of late\u2010onset HPP and pseudo\u2010HPP models. Moreover, alizarin red staining analysis showed that AAV8\u2010TNAP\u2010D<jats:sub>10<\/jats:sub> treatment did not promote ectopic calcification of soft organs in adult HPP mice after 60\u2009days of treatment, even after inducing chronic kidney disease. Overall, the AAV8\u2010TNAP\u2010D<jats:sub>10<\/jats:sub> treatment improved the skeletal phenotype in both the adult HPP and pseudo\u2010HPP mouse models. This preclinical study will contribute to the advancement of gene therapy for the improvement of skeletal disease in patients with heritable forms of osteomalacia. \u00a9 2022 The Authors. <jats:italic>JBMR Plus<\/jats:italic> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbm4.10709","type":"journal-article","created":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T07:29:10Z","timestamp":1669966150000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Gene Therapy Using Recombinant <scp>AAV<\/scp> Type 8 Vector Encoding <scp>TNAP\u2010D<sub>10<\/sub><\/scp> Improves the Skeletal Phenotypes in Murine Models of Osteomalacia"],"prefix":"10.1093","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3063-6694","authenticated-orcid":false,"given":"Flavia","family":"Amadeu de 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