Academic Journal
Coagulation factor IX gene transfer to non-human primates using engineered AAV3 capsid and hepatic optimized expression cassette
| العنوان: | Coagulation factor IX gene transfer to non-human primates using engineered AAV3 capsid and hepatic optimized expression cassette |
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| المؤلفون: | Sandeep R.P. Kumar, Jun Xie, Shilang Hu, Jihye Ko, Qifeng Huang, Harrison C. Brown, Alok Srivastava, David M. Markusic, Christopher B. Doering, H. Trent Spencer, Arun Srivastava, Guangping Gao, Roland W. Herzog |
| المصدر: | Molecular Therapy: Methods & Clinical Development, Vol 23, Iss , Pp 98-107 (2021) |
| بيانات النشر: | Elsevier, 2021. |
| سنة النشر: | 2021 |
| المجموعة: | LCC:Genetics LCC:Cytology |
| مصطلحات موضوعية: | adeno-associated virus, AAV, hemophilia, factor IX, liver, non-human primate, Genetics, QH426-470, Cytology, QH573-671 |
| الوصف: | Hepatic gene transfer with adeno-associated viral (AAV) vectors shows much promise for the treatment of the X-linked bleeding disorder hemophilia B in multiple clinical trials. In an effort to further innovate this approach and to introduce alternative vector designs with potentially superior features into clinical development, we recently built a vector platform based on AAV serotype 3 because of its superior tropism for human hepatocytes. A vector genome with serotype-matched inverted terminal repeats expressing hyperactive human coagulation factor IX (FIX)-Padua was designed for clinical use that is optimized for translation using hepatocyte-specific codon-usage bias and is depleted of immune stimulatory CpG motifs. Here, this vector genome was packaged into AAV3 (T492V + S663V) capsid for hepatic gene transfer in non-human primates. FIX activity within or near the normal range was obtained at a low vector dose of 5 × 1011 vector genomes/kg. Pre-existing neutralizing antibodies, however, completely or partially blocked hepatic gene transfer at that dose. No CD8+ T cell response against capsid was observed. Antibodies against the human FIX transgene product formed at a 10-fold higher vector dose, albeit hepatic gene transfer was remarkably consistent, and sustained FIX activity in the normal range was nonetheless achieved in two of three animals for the 3-month duration of the study. These results support the use of this vector at low vector doses for gene therapy of hemophilia B in humans. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2329-0501 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S2329050121001273; https://doaj.org/toc/2329-0501 |
| DOI: | 10.1016/j.omtm.2021.08.001 |
| URL الوصول: | https://doaj.org/article/c8c0531282d4473082e53448b9e6d260 |
| رقم الانضمام: | edsdoj.8c0531282d4473082e53448b9e6d260 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 23290501 |
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| DOI: | 10.1016/j.omtm.2021.08.001 |