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- Title
High-Level Expression of Alkaline Phosphatase by Adeno-Associated Virus Vector Ameliorates Pathological Bone Structure in a Hypophosphatasia Mouse Model.
- Authors
Nakamura-Takahashi, Aki; Tanase, Toshiki; Matsunaga, Satoru; Shintani, Seikou; Abe, Shinichi; Nitahara-Kasahara, Yuko; Watanabe, Atsushi; Hirai, Yukihiko; Okada, Takashi; Yamaguchi, Akira; Kasahara, Masataka
- Abstract
Hypophosphatasia (HPP) is a systemic skeletal disease caused by mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP). We recently reported that survival of HPP model mice can be prolonged using an adeno-associated virus (AAV) vector expressing bone-targeted TNALP with deca-aspartate at the C terminus (TNALP-D10); however, abnormal bone structure and hypomineralization remained in the treated mice. Here, to develop a more effective and clinically applicable approach, we assessed whether transfection with TNALP-D10 expressing virus vector at a higher dose than previously used would ameliorate bone structure defects. We constructed a self-complementary AAV8 vector expressing TNALP driven by the chicken beta-actin (CBA) promoter (scAAV8-CB-TNALP-D10). The vector was injected into both quadriceps femoris muscles of newborn HPP mice at a dose of 4.5 × 1012 vector genome (v.g.)/body, resulting in 20 U/mL of serum ALP activity. The 4.5 × 1012 v.g./body-treated HPP mice grew normally and displayed improved bone structure at the knee joints in X-ray images. Micro-CT analysis showed normal trabecular bone structure and mineralization. The mechanical properties of the femur were also recovered. Histological analysis of the femurs demonstrated that ALP replacement levels were sufficient to promote normal, growth plate cartilage arrangement. These results suggest that AAV vector-mediated high-dose TNALP-D10 therapy is a promising option for improving the quality of life (QOL) of patients with the infantile form of HPP.
- Subjects
BONES; ALKALINE phosphatase; ADENO-associated virus; GROWTH plate; GENETIC mutation; FEMUR; CARTILAGE; BIOLOGICAL models; RESEARCH; VIRUSES; ANIMAL experimentation; RESEARCH methodology; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; GENES; QUALITY of life; GENE therapy; INBORN errors of metabolism; METALS in the body; MICE
- Publication
Calcified Tissue International, 2020, Vol 106, Issue 6, p665
- ISSN
0171-967X
- Publication type
journal article
- DOI
10.1007/s00223-020-00676-5