High-Level Expression of Alkaline Phosphatase by Adeno-Associated Virus Vector Ameliorates Pathological Bone Structure in a Hypophosphatasia Mouse Model
| Autor: | Takashi Okada, Satoru Matsunaga, Aki Nakamura-Takahashi, Yuko Nitahara-Kasahara, Akira Yamaguchi, Seikou Shintani, Watanabe Atsushi, Masataka Kasahara, Toshiki Tanase, Shinichi Abe, Yukihiko Hirai |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Endocrinology Diabetes and Metabolism Genetic Vectors Hypophosphatasia Biology medicine.disease_cause Virus Viral vector Mice 03 medical and health sciences 0302 clinical medicine Endocrinology Internal medicine medicine Animals Orthopedics and Sports Medicine Abnormal bone structure Adeno-associated virus Genetic Therapy Transfection Enzyme replacement therapy Dependovirus Alkaline Phosphatase medicine.disease Disease Models Animal 030104 developmental biology Cancellous Bone Quality of Life Alkaline phosphatase 030217 neurology & neurosurgery |
| Zdroj: | Calcified tissue international. |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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