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Biodistribution and retargeting of FX-binding ablated adenovirus serotype 5 vectors.

Alba, R, Bradshaw, AC, Coughlan, L, Denby, L, McDonald, RA, Waddington, SN, Buckley, SM, Greig, JA, Parker, AL, Miller, AM , Wang, H, Lieber, A, van Rooijen, N, McVey, JH, Nicklin, SA and Baker, AH (2010) Biodistribution and retargeting of FX-binding ablated adenovirus serotype 5 vectors. Blood, 116 (15). pp. 2656-2664.

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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; 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.

Item Type: Article
Divisions : Surrey research (other units)
Authors :
Alba, R
Bradshaw, AC
Coughlan, L
Denby, L
McDonald, RA
Waddington, SN
Buckley, SM
Greig, JA
Parker, AL
Miller, AM
Wang, H
Lieber, A
van Rooijen, N
Nicklin, SA
Baker, AH
Date : 14 October 2010
DOI : 10.1182/blood-2009-12-260026
Uncontrolled Keywords : 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
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 09:56
Last Modified : 24 Jan 2020 18:05

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