دورية أكاديمية
Target-Cell-Directed Bioengineering Approaches for Gene Therapy of Hemophilia A
| العنوان: | Target-Cell-Directed Bioengineering Approaches for Gene Therapy of Hemophilia A |
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| المؤلفون: | Harrison C. Brown, Philip M. Zakas, Stephan N. George, Ernest T. Parker, H. Trent Spencer, Christopher B. Doering |
| المصدر: | Molecular Therapy: Methods & Clinical Development, Vol 9, Iss , Pp 57-69 (2018) |
| بيانات النشر: | Elsevier, 2018. |
| سنة النشر: | 2018 |
| المجموعة: | LCC:Genetics LCC:Cytology |
| مصطلحات موضوعية: | Genetics, QH426-470, Cytology, QH573-671 |
| الوصف: | Potency is a key optimization parameter for hemophilia A gene therapy product candidates. Optimization strategies include promoter engineering to increase transcription, codon optimization of mRNA to improve translation, and amino-acid substitution to promote secretion. Herein, we describe both rational and empirical design approaches to the development of a minimally sized, highly potent AAV-fVIII vector that incorporates three unique elements: a liver-directed 146-nt transcription regulatory module, a target-cell-specific codon optimization algorithm, and a high-expression bioengineered fVIII variant. The minimal synthetic promoter allows for the smallest AAV-fVIII vector genome known at 4,832 nt, while the tissue-directed codon optimization strategy facilitates increased fVIII transgene product expression in target cell types, e.g., hepatocytes, over traditional genome-level codon optimization strategies. As a tertiary approach, we incorporated ancient and orthologous fVIII sequence elements previously shown to facilitate improved biosynthesis through post-translational mechanisms. Together, these technologies contribute to an AAV-fVIII vector that confers sustained, curative levels of fVIII at a minimal dose in hemophilia A mice. Moreover, the first two technologies should be generalizable to all liver-directed gene therapy vector designs. Keywords: vector optimization, AAV, hemophilia, factor VIII, codon optimization, promoter design |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2329-0501 09423923 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S2329050118300056; https://doaj.org/toc/2329-0501 |
| DOI: | 10.1016/j.omtm.2018.01.004 |
| URL الوصول: | https://doaj.org/article/09423923e0794b1dacf97a03fa3b1882 |
| رقم الأكسشن: | edsdoj.09423923e0794b1dacf97a03fa3b1882 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 23290501 09423923 |
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| DOI: | 10.1016/j.omtm.2018.01.004 |