Efficient gene transduction in pigs and macaques with the engineered AAV vector AAV.GT5 for hemophilia B gene therapy
Gene therapy using adeno-associated virus (AAV)-based vectors has become a realistic therapeutic option for hemophilia. We examined the potential of a novel engineered liver-tropic AAV3B-based vector, AAV.GT5, for hemophilia B gene therapy. In vitro transduction with AAV.GT5 in human hepatocytes was...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050123001304 |
| _version_ | 1797706888935112704 |
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| author | Yuji Kashiwakura Kazuhiro Endo Atsushi Ugajin Tomohiro Kikuchi Shuji Hishikawa Hitoyasu Nakamura Yuko Katakai Nemekhbayar Baatartsogt Takafumi Hiramoto Morisada Hayakawa Nobuhiko Kamoshita Shoji Yamazaki Akihiro Kume Harushi Mori Naohiro Sata Yoichi Sakata Shin-ichi Muramatsu Tsukasa Ohmori |
| author_facet | Yuji Kashiwakura Kazuhiro Endo Atsushi Ugajin Tomohiro Kikuchi Shuji Hishikawa Hitoyasu Nakamura Yuko Katakai Nemekhbayar Baatartsogt Takafumi Hiramoto Morisada Hayakawa Nobuhiko Kamoshita Shoji Yamazaki Akihiro Kume Harushi Mori Naohiro Sata Yoichi Sakata Shin-ichi Muramatsu Tsukasa Ohmori |
| author_sort | Yuji Kashiwakura |
| collection | DOAJ |
| description | Gene therapy using adeno-associated virus (AAV)-based vectors has become a realistic therapeutic option for hemophilia. We examined the potential of a novel engineered liver-tropic AAV3B-based vector, AAV.GT5, for hemophilia B gene therapy. In vitro transduction with AAV.GT5 in human hepatocytes was more than 100 times higher than with AAV-Spark100, another bioengineered vector used in a clinical trial. However, liver transduction following intravenous injection of these vectors was similar in mice with a humanized liver and in macaques. This discrepancy was due to the low recovery and short half-life of AAV.GT5 in blood, depending on the positive charge of the heparin-binding site in the capsid. Bypassing systemic clearance with the intra-hepatic vascular administration of AAV.GT5, but not AAV-Spark100, enhanced liver transduction in pigs and macaques. AAV.GT5 did not develop neutralizing antibodies (NAbs) in two of four animals, while AAV-Spark100 induced serotype-specific NAbs in all macaques tested (4 of 4). The NAbs produced after AAV-Spark100 administration were relatively serotype specific, and challenge with AAV.GT5 through the hepatic artery successfully boosted liver transduction in one animal previously administered AAV-Spark100. In summary, AAV.GT5 showed different vector kinetics and NAb induction compared with AAV-Spark100, and intra-hepatic vascular administration may minimize the vector dose required and vector dissemination. |
| first_indexed | 2024-03-12T05:59:02Z |
| format | Article |
| id | doaj.art-e60d3f3fd02c459c99665b37f69364fb |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-03-12T05:59:02Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-e60d3f3fd02c459c99665b37f69364fb2023-09-03T04:24:00ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012023-09-0130502514Efficient gene transduction in pigs and macaques with the engineered AAV vector AAV.GT5 for hemophilia B gene therapyYuji Kashiwakura0Kazuhiro Endo1Atsushi Ugajin2Tomohiro Kikuchi3Shuji Hishikawa4Hitoyasu Nakamura5Yuko Katakai6Nemekhbayar Baatartsogt7Takafumi Hiramoto8Morisada Hayakawa9Nobuhiko Kamoshita10Shoji Yamazaki11Akihiro Kume12Harushi Mori13Naohiro Sata14Yoichi Sakata15Shin-ichi Muramatsu16Tsukasa Ohmori17Department of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDepartment of Surgery, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Center for Development of Advanced Medical Technology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDepartment of Radiology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDepartment of Radiology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDepartment of Surgery, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Center for Development of Advanced Medical Technology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDepartment of Radiology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanThe Corporation for Production and Research of Laboratory Primates, 1-16-2 Sakura, Tsukuba, Ibaraki 305-0003, JapanDepartment of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDepartment of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDepartment of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Center for Gene Therapy Research, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDepartment of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Center for Gene Therapy Research, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanClinical Research Center, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanCenter for Gene Therapy Research, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Clinical Research Center, Jichi Medical University Hospital, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDepartment of Radiology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDepartment of Surgery, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Center for Development of Advanced Medical Technology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanDepartment of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, JapanCenter for Gene Therapy Research, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Division of Neurological Gene Therapy, Center for Open Innovation, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Center for Gene and Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, JapanDepartment of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Center for Gene Therapy Research, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan; Corresponding author: Tsukasa Ohmori, Department of Biochemistry, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.Gene therapy using adeno-associated virus (AAV)-based vectors has become a realistic therapeutic option for hemophilia. We examined the potential of a novel engineered liver-tropic AAV3B-based vector, AAV.GT5, for hemophilia B gene therapy. In vitro transduction with AAV.GT5 in human hepatocytes was more than 100 times higher than with AAV-Spark100, another bioengineered vector used in a clinical trial. However, liver transduction following intravenous injection of these vectors was similar in mice with a humanized liver and in macaques. This discrepancy was due to the low recovery and short half-life of AAV.GT5 in blood, depending on the positive charge of the heparin-binding site in the capsid. Bypassing systemic clearance with the intra-hepatic vascular administration of AAV.GT5, but not AAV-Spark100, enhanced liver transduction in pigs and macaques. AAV.GT5 did not develop neutralizing antibodies (NAbs) in two of four animals, while AAV-Spark100 induced serotype-specific NAbs in all macaques tested (4 of 4). The NAbs produced after AAV-Spark100 administration were relatively serotype specific, and challenge with AAV.GT5 through the hepatic artery successfully boosted liver transduction in one animal previously administered AAV-Spark100. In summary, AAV.GT5 showed different vector kinetics and NAb induction compared with AAV-Spark100, and intra-hepatic vascular administration may minimize the vector dose required and vector dissemination.http://www.sciencedirect.com/science/article/pii/S2329050123001304gene therapyhemophilia Badeno-associated virus vectorsvector recoverabilityintra-hepatic vascular administration |
| spellingShingle | Yuji Kashiwakura Kazuhiro Endo Atsushi Ugajin Tomohiro Kikuchi Shuji Hishikawa Hitoyasu Nakamura Yuko Katakai Nemekhbayar Baatartsogt Takafumi Hiramoto Morisada Hayakawa Nobuhiko Kamoshita Shoji Yamazaki Akihiro Kume Harushi Mori Naohiro Sata Yoichi Sakata Shin-ichi Muramatsu Tsukasa Ohmori Efficient gene transduction in pigs and macaques with the engineered AAV vector AAV.GT5 for hemophilia B gene therapy Molecular Therapy: Methods & Clinical Development gene therapy hemophilia B adeno-associated virus vectors vector recoverability intra-hepatic vascular administration |
| title | Efficient gene transduction in pigs and macaques with the engineered AAV vector AAV.GT5 for hemophilia B gene therapy |
| title_full | Efficient gene transduction in pigs and macaques with the engineered AAV vector AAV.GT5 for hemophilia B gene therapy |
| title_fullStr | Efficient gene transduction in pigs and macaques with the engineered AAV vector AAV.GT5 for hemophilia B gene therapy |
| title_full_unstemmed | Efficient gene transduction in pigs and macaques with the engineered AAV vector AAV.GT5 for hemophilia B gene therapy |
| title_short | Efficient gene transduction in pigs and macaques with the engineered AAV vector AAV.GT5 for hemophilia B gene therapy |
| title_sort | efficient gene transduction in pigs and macaques with the engineered aav vector aav gt5 for hemophilia b gene therapy |
| topic | gene therapy hemophilia B adeno-associated virus vectors vector recoverability intra-hepatic vascular administration |
| url | http://www.sciencedirect.com/science/article/pii/S2329050123001304 |
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