دورية أكاديمية
Efficient gene transduction in pigs and macaques with the engineered AAV vector AAV.GT5 for hemophilia B gene therapy
| العنوان: | Efficient gene transduction in pigs and macaques with the engineered AAV vector AAV.GT5 for hemophilia B gene therapy |
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| المؤلفون: | 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 |
| المصدر: | Molecular Therapy: Methods & Clinical Development, Vol 30, Iss , Pp 502-514 (2023) |
| بيانات النشر: | Elsevier, 2023. |
| سنة النشر: | 2023 |
| المجموعة: | LCC:Genetics LCC:Cytology |
| مصطلحات موضوعية: | gene therapy, hemophilia B, adeno-associated virus vectors, vector recoverability, intra-hepatic vascular administration, Genetics, QH426-470, Cytology, QH573-671 |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2329-0501 |
| العلاقة: | http://www.sciencedirect.com/science/article/pii/S2329050123001304Test; https://doaj.org/toc/2329-0501Test |
| DOI: | 10.1016/j.omtm.2023.08.016 |
| الوصول الحر: | https://doaj.org/article/e60d3f3fd02c459c99665b37f69364fbTest |
| رقم الانضمام: | edsdoj.60d3f3fd02c459c99665b37f69364fb |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 23290501 |
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| DOI: | 10.1016/j.omtm.2023.08.016 |