Journal
BLOOD
Volume 116, Issue 15, Pages 2656-2664Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-12-260026
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Funding
- Biotechnology and Biological Sciences Research Council
- British Heart Foundation
- BHF
- Royal Society of Edinburgh Scotland Foundation
- BBSRC [BB/E02145X/1, BB/E02145X/2, BB/E021301/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/E021301/1, BB/E02145X/2, BB/E02145X/1] Funding Source: researchfish
- British Heart Foundation [RG/09/005/27915] Funding Source: researchfish
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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; how-ever, 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. (Blood. 2010;116(15):2656-2664)
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