Abstract
A major limitation for adenoviral transduction in vivo is the profound liver tropism of adenovirus type 5 (Ad5). Recently, we demonstrated that coagulation factor X (FX) binds to Ad5-hexon protein at high affinity to mediate hepatocyte transduction after intravascular delivery. We developed novel genetically FX-binding ablated Ad5 vectors with lower liver transduction. Here, we demonstrate that FX-binding ablated Ad5 predominantly localize to the liver and spleen 1 hour after injection; however, they had highly reduced liver transduction in both control and macrophage-depleted mice compared with Ad5. At high doses in macrophage-depleted mice, FX-binding ablated vectors transduced the spleen more efficiently than Ad5. Immunohistochemical studies demonstrated transgene colocalization with CD11c(+), ER-TR7(+), and MAdCAM-1(+) cells in the splenic marginal zone. Systemic inflammatory profiles were broadly similar between FX-binding ablated Ad5 and Ad5 at low and intermediate doses, although higher levels of several inflammatory proteins were observed at the highest dose of FX-binding ablated Ad5. Subsequently, we generated a FX-binding ablated virus containing a high affinity Ad35 fiber that mediated a significant improvement in lung/liver ratio in macrophage-depleted CD46(+) mice compared with controls. Therefore, this study documents the biodistribution and reports the retargeting capacity of FX binding-ablated Ad5 vectors in vitro and in vivo.
Original language | English |
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Pages (from-to) | 2656-64 |
Number of pages | 9 |
Journal | Blood |
Volume | 116 |
Issue number | 15 |
DOIs | |
Publication status | Published - 14 Oct 2010 |
Keywords / Materials (for Non-textual outputs)
- Adenoviruses, Human
- Animals
- Capsid Proteins
- Chemokines
- Cytokines
- Factor X
- Genetic Vectors
- Humans
- Inflammation Mediators
- Liver
- Lung
- Male
- Mice
- Mice, Transgenic
- Protein Binding
- Recombinant Proteins
- Serotyping
- Spleen
- Time Factors
- Tissue Distribution
- Transduction, Genetic
- beta-Galactosidase