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Bone-Targeted Alkaline Phosphatase Treatment of Mandibular Bone and Teeth in Lethal Hypophosphatasia via an scAAV8 Vector

Hypophosphatasia is an inherited disease caused by mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP), the major symptom of which is hypomineralization of the bones and teeth. We had recently demonstrated that TNALP-deficient (Akp2(−/−)) mice, which mimic the phenotype of...

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Autores principales: Ikeue, Ryo, Nakamura-Takahashi, Aki, Nitahara-Kasahara, Yuko, Watanabe, Atsushi, Muramatsu, Takashi, Sato, Toru, Okada, Takashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129726/
https://www.ncbi.nlm.nih.gov/pubmed/30202773
http://dx.doi.org/10.1016/j.omtm.2018.08.004
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author Ikeue, Ryo
Nakamura-Takahashi, Aki
Nitahara-Kasahara, Yuko
Watanabe, Atsushi
Muramatsu, Takashi
Sato, Toru
Okada, Takashi
author_facet Ikeue, Ryo
Nakamura-Takahashi, Aki
Nitahara-Kasahara, Yuko
Watanabe, Atsushi
Muramatsu, Takashi
Sato, Toru
Okada, Takashi
author_sort Ikeue, Ryo
collection PubMed
description Hypophosphatasia is an inherited disease caused by mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP), the major symptom of which is hypomineralization of the bones and teeth. We had recently demonstrated that TNALP-deficient (Akp2(−/−)) mice, which mimic the phenotype of the severe infantile form of hypophosphatasia, can be treated by intramuscular injection of a self-complementary (sc) type 8 recombinant adeno-associated virus (rAAV8) vector expressing bone-targeted TNALP with deca-aspartates at the C terminus (TNALP-D(10)) via the muscle creatine kinase (MCK) promoter. In this study, we focused on the efficacy of this scAAV8-MCK-TNALP-D(10) treatment on the mandibular bone and teeth in neonatal Akp2(−/−) mice. Upon scAAV8-MCK-TNALP-D(10) injection, an improvement of mandibular growth was observed by X-ray analysis. Micro-computed tomography analysis revealed progressive mineralization of the molar root in the treated Akp2(−/−) mice, and morphometric parameters of the alveolar bone were improved. These results suggest that the mandibular bones and teeth of hypophosphatasia were effectively treated by muscle directed rAAV-mediated TNALP-D(10) transduction. Our strategy would be promising for future hypophosphatasia gene therapy because it induces dentoalveolar mineralization and reduces the risk of tooth exfoliation.
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spelling pubmed-61297262018-09-10 Bone-Targeted Alkaline Phosphatase Treatment of Mandibular Bone and Teeth in Lethal Hypophosphatasia via an scAAV8 Vector Ikeue, Ryo Nakamura-Takahashi, Aki Nitahara-Kasahara, Yuko Watanabe, Atsushi Muramatsu, Takashi Sato, Toru Okada, Takashi Mol Ther Methods Clin Dev Article Hypophosphatasia is an inherited disease caused by mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP), the major symptom of which is hypomineralization of the bones and teeth. We had recently demonstrated that TNALP-deficient (Akp2(−/−)) mice, which mimic the phenotype of the severe infantile form of hypophosphatasia, can be treated by intramuscular injection of a self-complementary (sc) type 8 recombinant adeno-associated virus (rAAV8) vector expressing bone-targeted TNALP with deca-aspartates at the C terminus (TNALP-D(10)) via the muscle creatine kinase (MCK) promoter. In this study, we focused on the efficacy of this scAAV8-MCK-TNALP-D(10) treatment on the mandibular bone and teeth in neonatal Akp2(−/−) mice. Upon scAAV8-MCK-TNALP-D(10) injection, an improvement of mandibular growth was observed by X-ray analysis. Micro-computed tomography analysis revealed progressive mineralization of the molar root in the treated Akp2(−/−) mice, and morphometric parameters of the alveolar bone were improved. These results suggest that the mandibular bones and teeth of hypophosphatasia were effectively treated by muscle directed rAAV-mediated TNALP-D(10) transduction. Our strategy would be promising for future hypophosphatasia gene therapy because it induces dentoalveolar mineralization and reduces the risk of tooth exfoliation. American Society of Gene & Cell Therapy 2018-08-18 /pmc/articles/PMC6129726/ /pubmed/30202773 http://dx.doi.org/10.1016/j.omtm.2018.08.004 Text en © 2018 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ikeue, Ryo
Nakamura-Takahashi, Aki
Nitahara-Kasahara, Yuko
Watanabe, Atsushi
Muramatsu, Takashi
Sato, Toru
Okada, Takashi
Bone-Targeted Alkaline Phosphatase Treatment of Mandibular Bone and Teeth in Lethal Hypophosphatasia via an scAAV8 Vector
title Bone-Targeted Alkaline Phosphatase Treatment of Mandibular Bone and Teeth in Lethal Hypophosphatasia via an scAAV8 Vector
title_full Bone-Targeted Alkaline Phosphatase Treatment of Mandibular Bone and Teeth in Lethal Hypophosphatasia via an scAAV8 Vector
title_fullStr Bone-Targeted Alkaline Phosphatase Treatment of Mandibular Bone and Teeth in Lethal Hypophosphatasia via an scAAV8 Vector
title_full_unstemmed Bone-Targeted Alkaline Phosphatase Treatment of Mandibular Bone and Teeth in Lethal Hypophosphatasia via an scAAV8 Vector
title_short Bone-Targeted Alkaline Phosphatase Treatment of Mandibular Bone and Teeth in Lethal Hypophosphatasia via an scAAV8 Vector
title_sort bone-targeted alkaline phosphatase treatment of mandibular bone and teeth in lethal hypophosphatasia via an scaav8 vector
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129726/
https://www.ncbi.nlm.nih.gov/pubmed/30202773
http://dx.doi.org/10.1016/j.omtm.2018.08.004
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