Characterization of Adeno-Associated Viral Vector-Mediated Human Factor VIII Gene Therapy in Hemophilia A Mice
| Autor: | Amanda L. Reicherter, Alexandra L. Hanlon, K. Reed Clark, Christopher H. Tipper, James M. Wilson, Lili Wang, Qiang Wang, Jenny A. Greig, Shu-Jen Chen, Samuel C. Wadsworth |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Transgene Genetic enhancement Genetic Vectors Biology Hemophilia A Genome Viral vector 03 medical and health sciences Mice Genetics Immune Tolerance Animals Humans Vector (molecular biology) Transgenes Enhancer Promoter Regions Genetic Molecular Biology Mice Knockout Factor VIII Gene Transfer Techniques Promoter Genetic Therapy Dependovirus Virology Disease Models Animal 030104 developmental biology Capsid Gene Expression Regulation Liver Molecular Medicine Capsid Proteins |
| Zdroj: | Human gene therapy. 28(5) |
| ISSN: | 1557-7422 |
| Popis: | Adeno-associated viral (AAV) vectors are promising vehicles for hemophilia gene therapy, with favorable clinical trial data seen in the treatment of hemophilia B. In an effort to optimize the expression of human coagulation factor VIII (hFVIII) for the treatment of hemophilia A, an extensive study was performed with numerous combinations of liver-specific promoter and enhancer elements with a codon-optimized hFVIII transgene. After generating 42 variants of three reduced-size promoters and three small enhancers, transgene cassettes were packaged within a single AAV capsid, AAVrh10, to eliminate performance differences due to the capsid type. Each hFVIII vector was administered to FVIII knockout (KO) mice at a dose of 1010 genome copies (GC) per mouse. Criteria for distinguishing the performance of the different enhancer/promoter combinations were established prior to the initiation of the studies. These criteria included prominently the level of hFVIII activity (0.12–2.12 IU/mL) and the pattern of develop... |
| Databáze: | OpenAIRE |
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