Posted at the Institutional Resources for Unique Collection and Academic Archives at Tokyo Dental College, Available from http://ir.tdc.ac.jp/
Title Gene therapy for hypophosphatasia Author(s) Aki, Nakamura‑Takahashi
Journal 歯科学報, 121(4): 418‑419
URL http://hdl.handle.net/10130/5741 Right
Description
Hypophosphatasia（HPP）is a systemic skeletal disease caused by mutations in the gene encoding tissue- nonspecific alkaline phosphatase（TNALP）.Although considerable amount of attention has been focused on the enzyme replacement therapy ERT as a Breakthrough therapy , repeated injections of large amounts of recombinant TNALP are required to achieve clinical benefits. As an alternative approach, we recently re- ported that survival of HPP mice（Akp２−／−mice）can be prolonged by a single injection of adeno-associated virus（AAV）vector mediating the expression of TNALP. Nevertheless, treated mice still presented abnor- mal structure of hard tissue. Therefore, we assessed the efficacy of ALP replacement closer to optimal lev- els on the recovery of the bone structure. The result showed that the higher-dose treated mice were nor- mal femur lengths and body weight. There was no significant difference in the femur bone mineral density between higher-dose treated mice and Akp２＋／＋mice. Histological analysis of the femurs on the higher-dose treated mice showed increase of ALP replacement and reduced of abnormal chondrocytes．
These results suggest that AAV-mediated high-dose ALP replacement strategy is a promising option for the improvement of the QOL of HPP patients. In this session, we would like to discuss gene therapy for sys- temic bone disease and introduce our recent findings and recent information．
Tokyo Dental College Research Branding Project Asian Rising Star Symposium 2021
Gene therapy for hypophosphatasia
Aki Nakamura-Takahashi, DDS, PhD
Lecturer
Department of Pharmacology, Tokyo Dental College
顎骨疾患プロジェクト国際シンポジウム
学 会 講 演 抄 録 ４１８
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Curriculum Vitae
２０１１ DDS, Tokyo Dental College, Japan
２０１６ PhD, Nippon Medical School, Japan（Biochemistry and Molecular Biology）
２０１６ Assistant Professor, Dept. of Pharmacology, Tokyo Dental College, Japan ２０２１ Lecturer, Dept. of Pharmacology, Tokyo Dental College, Japan
Honors
２０１５：JSGCT ２１th Annual Meeting-Young Investigatorʼs Award
Research Fields of Interest
Gene therapy, Hypophosphatasia, Congenital disease
Selected Publications
１．Hasegawa A, Takahashi AN, Kasahara M, Saso N, Narisawa S, Millán JL, Samura O, Sago H, Okamoto A, Umezawa A. Prenatal enzyme replacement therapy for Akp２−／−mice with lethal Hypophosphatasia.
Regen Ther．２０２１;１８：１６８−１７５．
２．Kasahara YN, Kuraoka M, Posadas HG, Kinoh HH, Maruoka Y, Takahashi AN, Kimura K, Takeda S, Okada T. Dental pulp stem cells can improve muscle dysfunction in animal models of Duchenne muscular dystrophy.Stem Cell Res Ther．２０２１;１２⑴：７８．
３．Takahashi AN, Tanase T, Matsunaga S, Shintani S, Abe S, Kasahara YN, Watanabe A, Hirai Y, Okada T, Yamaguchi A, Kasahara M. High-level expression of alkaline phosphatase by adeno-associated virus vector ameliorates pathological bone structure in a hypophosphatasia mouse model. Calcif Tissue Int．２０２０；１０６⑹：６６５−６７７．
４．Nakamura T,Takahashi AN, Kasahara M, Komori T, Yamaguchi A, Azuma T. Tissue- Nonspecific alka- line phosphatase promotes osteogenic differentiation of bone mesenchymal stem cell. Biochem Biophys Res Commun．２０２０；５２４⑶：７０２−７０９．
５．Kosugi A, Kasahara M, Yang L, Takahashi AN, Shibahara T, Mori T : Method for diagnosing neoplastic lesions by quantitative fluorescence value.Sci Rep．２０１９；９⑴：７８３３．
６．Ikeue R,Takahashi AN, Kasahara YN, Watanabe A, Muramatsu T, Sato T, Okada T：Bone-targeted al- kaline phosphatase treatment of mandibular bone and teeth in lethal hypophosphatasia via an scAAV８ vector.Mol Ther Methods Clin．２０１８；１０：３６１−３７０．
７．Takahashi AN, Miyake K, Watanabe A, Hirai Y, Iijima O, Miyake N, Adachi K, Kasahara YN, Kinoshita H, Noguchi T, Abe S, Narisawa S, Millán JN, Shimada T, Okada T：Treatment of hypophosphatasia by muscle−directed expression of bone-targeted alkaline phosphatase via self-complementary AAV８ vec- tor.Mol Ther Methods Clin．２０１６；３：１−９．
歯科学報 Vol．１２１，No．４（２０２２） ４１９
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