論文

査読有り 国際誌
2018年9月21日

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

Molecular therapy. Methods & clinical development
  • Ryo Ikeue
  • ,
  • Aki Nakamura-Takahashi
  • ,
  • Yuko Nitahara-Kasahara
  • ,
  • Atsushi Watanabe
  • ,
  • Takashi Muramatsu
  • ,
  • Toru Sato
  • ,
  • Takashi Okada

10
開始ページ
361
終了ページ
370
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.omtm.2018.08.004

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-D10) via the muscle creatine kinase (MCK) promoter. In this study, we focused on the efficacy of this scAAV8-MCK-TNALP-D10 treatment on the mandibular bone and teeth in neonatal Akp2
-/-
mice. Upon scAAV8-MCK-TNALP-D10 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-D10 transduction. Our strategy would be promising for future hypophosphatasia gene therapy because it induces dentoalveolar mineralization and reduces the risk of tooth exfoliation.

リンク情報
DOI
https://doi.org/10.1016/j.omtm.2018.08.004
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/30202773
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129726

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