Treatment of hypophosphatasia by muscle-directed expression of bone-targeted alkaline phosphatase via self-complementary AAV8 vector
Hypophosphatasia (HPP) is an inherited disease caused by genetic mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP). This results in defects in bone and tooth mineralization. We recently demonstrated that TNALP-deficient (Akp2−/−) mice, which mimic the phenotype of the se...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-01-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050116301498 |
| _version_ | 1818174292579319808 |
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| author | Aki Nakamura-Takahashi Koichi Miyake Atsushi Watanabe Yukihiko Hirai Osamu Iijima Noriko Miyake Kumi Adachi Yuko Nitahara-Kasahara Hideaki Kinoshita Taku Noguchi Shinichi Abe Sonoko Narisawa Jose Luis Millán Takashi Shimada Takashi Okada |
| author_facet | Aki Nakamura-Takahashi Koichi Miyake Atsushi Watanabe Yukihiko Hirai Osamu Iijima Noriko Miyake Kumi Adachi Yuko Nitahara-Kasahara Hideaki Kinoshita Taku Noguchi Shinichi Abe Sonoko Narisawa Jose Luis Millán Takashi Shimada Takashi Okada |
| author_sort | Aki Nakamura-Takahashi |
| collection | DOAJ |
| description | Hypophosphatasia (HPP) is an inherited disease caused by genetic mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP). This results in defects in bone and tooth mineralization. We recently demonstrated that TNALP-deficient (Akp2−/−) mice, which mimic the phenotype of the severe infantile form of HPP, can be treated by intravenous injection of a recombinant adeno-associated virus (rAAV) expressing bone-targeted TNALP with deca-aspartates at the C-terminus (TNALP-D10) driven by the tissue-nonspecific CAG promoter. To develop a safer and more clinically applicable transduction strategy for HPP gene therapy, we constructed a self-complementary type 8 AAV (scAAV8) vector that expresses TNALP-D10 via the muscle creatine kinase (MCK) promoter (scAAV8-MCK-TNALP-D10) and examined the efficacy of muscle-directed gene therapy. When scAAV8-MCK-TNALP-D10 was injected into the bilateral quadriceps of neonatal Akp2−/− mice, the treated mice grew well and survived for more than 3 months, with a healthy appearance and normal locomotion. Improved bone architecture, but limited elongation of the long bone, was demonstrated on X-ray images. Micro-CT analysis showed hypomineralization and abnormal architecture of the trabecular bone in the epiphysis. These results suggest that rAAV-mediated, muscle-specific expression of TNALP-D10 represents a safe and practical option to treat the severe infantile form of HPP. |
| first_indexed | 2024-12-11T19:42:05Z |
| format | Article |
| id | doaj.art-b854796ff45a455191ade5d1a6c16743 |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-11T19:42:05Z |
| publishDate | 2016-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-b854796ff45a455191ade5d1a6c167432022-12-22T00:52:59ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012016-01-013C10.1038/mtm.2015.59Treatment of hypophosphatasia by muscle-directed expression of bone-targeted alkaline phosphatase via self-complementary AAV8 vectorAki Nakamura-Takahashi0Koichi Miyake1Atsushi Watanabe2Yukihiko Hirai3Osamu Iijima4Noriko Miyake5Kumi Adachi6Yuko Nitahara-Kasahara7Hideaki Kinoshita8Taku Noguchi9Shinichi Abe10Sonoko Narisawa11Jose Luis Millán12Takashi Shimada13Takashi Okada14Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, JapanDepartment of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, JapanDepartment of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, JapanDepartment of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, JapanDepartment of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, JapanDepartment of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, JapanDepartment of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, JapanDepartment of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, JapanDepartment of Dental Materials Science, Tokyo Dental College, Tokyo, JapanDepartment of Anatomy, Tokyo Dental College, Tokyo, JapanDepartment of Anatomy, Tokyo Dental College, Tokyo, JapanSanford Children's Health Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, California, USASanford Children's Health Research Center, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, California, USADepartment of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, JapanDepartment of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, JapanHypophosphatasia (HPP) is an inherited disease caused by genetic mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP). This results in defects in bone and tooth mineralization. We recently demonstrated that TNALP-deficient (Akp2−/−) mice, which mimic the phenotype of the severe infantile form of HPP, can be treated by intravenous injection of a recombinant adeno-associated virus (rAAV) expressing bone-targeted TNALP with deca-aspartates at the C-terminus (TNALP-D10) driven by the tissue-nonspecific CAG promoter. To develop a safer and more clinically applicable transduction strategy for HPP gene therapy, we constructed a self-complementary type 8 AAV (scAAV8) vector that expresses TNALP-D10 via the muscle creatine kinase (MCK) promoter (scAAV8-MCK-TNALP-D10) and examined the efficacy of muscle-directed gene therapy. When scAAV8-MCK-TNALP-D10 was injected into the bilateral quadriceps of neonatal Akp2−/− mice, the treated mice grew well and survived for more than 3 months, with a healthy appearance and normal locomotion. Improved bone architecture, but limited elongation of the long bone, was demonstrated on X-ray images. Micro-CT analysis showed hypomineralization and abnormal architecture of the trabecular bone in the epiphysis. These results suggest that rAAV-mediated, muscle-specific expression of TNALP-D10 represents a safe and practical option to treat the severe infantile form of HPP.http://www.sciencedirect.com/science/article/pii/S2329050116301498 |
| spellingShingle | Aki Nakamura-Takahashi Koichi Miyake Atsushi Watanabe Yukihiko Hirai Osamu Iijima Noriko Miyake Kumi Adachi Yuko Nitahara-Kasahara Hideaki Kinoshita Taku Noguchi Shinichi Abe Sonoko Narisawa Jose Luis Millán Takashi Shimada Takashi Okada Treatment of hypophosphatasia by muscle-directed expression of bone-targeted alkaline phosphatase via self-complementary AAV8 vector Molecular Therapy: Methods & Clinical Development |
| title | Treatment of hypophosphatasia by muscle-directed expression of bone-targeted alkaline phosphatase via self-complementary AAV8 vector |
| title_full | Treatment of hypophosphatasia by muscle-directed expression of bone-targeted alkaline phosphatase via self-complementary AAV8 vector |
| title_fullStr | Treatment of hypophosphatasia by muscle-directed expression of bone-targeted alkaline phosphatase via self-complementary AAV8 vector |
| title_full_unstemmed | Treatment of hypophosphatasia by muscle-directed expression of bone-targeted alkaline phosphatase via self-complementary AAV8 vector |
| title_short | Treatment of hypophosphatasia by muscle-directed expression of bone-targeted alkaline phosphatase via self-complementary AAV8 vector |
| title_sort | treatment of hypophosphatasia by muscle directed expression of bone targeted alkaline phosphatase via self complementary aav8 vector |
| url | http://www.sciencedirect.com/science/article/pii/S2329050116301498 |
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