Retargeting of gene expression using endothelium specific hexon modified adenoviral vector

Sergey A. Kaliberov; Lyudmila N. Kaliberova; Zhi Hong Lu; Meredith A. Preuss; Justin A. Barnes; Cecil R. Stockard; William E. Grizzle; Jeffrey M. Arbeit; David T. Curiel

doi:10.1016/j.virol.2013.09.020

Retargeting of gene expression using endothelium specific hexon modified adenoviral vector

Sergey A. Kaliberov, Lyudmila N. Kaliberova, Zhi Hong Lu, Meredith A. Preuss, Justin A. Barnes, Cecil R. Stockard, William E. Grizzle, Jeffrey M. Arbeit, David T. Curiel

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

Adenovirus serotype 5 (Ad5) vectors are well suited for gene therapy. However, tissue-selective transduction by systemically administered Ad5-based vectors is confounded by viral particle sequestration in the liver. Hexon-modified Ad5 expressing reporter gene under transcriptional control by the immediate/early cytomegalovirus (CMV) or the Roundabout 4 receptor (Robo4) enhancer/promoter was characterized by growth in cell culture, stability in vitro, gene transfer in the presence of human coagulation factor X, and biodistribution in mice. The obtained data demonstrate the utility of the Robo4 promoter in an Ad5 vector context. Substitution of the hypervariable region 7 (HVR7) of the Ad5 hexon with HVR7 from Ad serotype 3 resulted in decreased liver tropism and dramatically altered biodistribution of gene expression. The results of these studies suggest that the combination of liver detargeting using a genetic modification of hexon with an endothelium-specific transcriptional control element produces an additive effect in the improvement of Ad5 biodistribution.

Original language	English
Pages (from-to)	312-325
Number of pages	14
Journal	Virology
Volume	447
Issue number	1-2
DOIs	https://doi.org/10.1016/j.virol.2013.09.020
State	Published - Dec 2013

Keywords

Adenovirus
Endothelium
Hexon
Roundabout 4 promoter
Targeting

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10.1016/j.virol.2013.09.020

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@article{631afe74e61f4f56a0da3c8c8934eae2,

title = "Retargeting of gene expression using endothelium specific hexon modified adenoviral vector",

abstract = "Adenovirus serotype 5 (Ad5) vectors are well suited for gene therapy. However, tissue-selective transduction by systemically administered Ad5-based vectors is confounded by viral particle sequestration in the liver. Hexon-modified Ad5 expressing reporter gene under transcriptional control by the immediate/early cytomegalovirus (CMV) or the Roundabout 4 receptor (Robo4) enhancer/promoter was characterized by growth in cell culture, stability in vitro, gene transfer in the presence of human coagulation factor X, and biodistribution in mice. The obtained data demonstrate the utility of the Robo4 promoter in an Ad5 vector context. Substitution of the hypervariable region 7 (HVR7) of the Ad5 hexon with HVR7 from Ad serotype 3 resulted in decreased liver tropism and dramatically altered biodistribution of gene expression. The results of these studies suggest that the combination of liver detargeting using a genetic modification of hexon with an endothelium-specific transcriptional control element produces an additive effect in the improvement of Ad5 biodistribution.",

keywords = "Adenovirus, Endothelium, Hexon, Roundabout 4 promoter, Targeting",

author = "Kaliberov, {Sergey A.} and Kaliberova, {Lyudmila N.} and {Hong Lu}, Zhi and Preuss, {Meredith A.} and Barnes, {Justin A.} and Stockard, {Cecil R.} and Grizzle, {William E.} and Arbeit, {Jeffrey M.} and Curiel, {David T.}",

note = "Funding Information: The authors are grateful to William C. Aird and Yoshiaki Okada from the Center for Vascular Biology Research, Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, for providing the Robo4 promoter. The authors thank Dr. Hongju Wu from Tulane University, New Orleans, LA, and Dr. Andrew H. Baker from University of Glasgow, Glasgow, UK, for providing the pAd5/H3GL and pAd5 ⁎ 7 ⁎ plasmids, respectively. This work was supported in part by National Heart, Lung and Blood Institute grant 5R01HL092941-02 and National Cancer Institute grant CA154697 .",

year = "2013",

month = dec,

doi = "10.1016/j.virol.2013.09.020",

language = "English",

volume = "447",

pages = "312--325",

journal = "Virology",

issn = "0042-6822",

number = "1-2",

}

TY - JOUR

T1 - Retargeting of gene expression using endothelium specific hexon modified adenoviral vector

AU - Kaliberov, Sergey A.

AU - Kaliberova, Lyudmila N.

AU - Hong Lu, Zhi

AU - Preuss, Meredith A.

AU - Barnes, Justin A.

AU - Stockard, Cecil R.

AU - Grizzle, William E.

AU - Arbeit, Jeffrey M.

AU - Curiel, David T.

N1 - Funding Information: The authors are grateful to William C. Aird and Yoshiaki Okada from the Center for Vascular Biology Research, Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, for providing the Robo4 promoter. The authors thank Dr. Hongju Wu from Tulane University, New Orleans, LA, and Dr. Andrew H. Baker from University of Glasgow, Glasgow, UK, for providing the pAd5/H3GL and pAd5 ⁎ 7 ⁎ plasmids, respectively. This work was supported in part by National Heart, Lung and Blood Institute grant 5R01HL092941-02 and National Cancer Institute grant CA154697 .

PY - 2013/12

Y1 - 2013/12

N2 - Adenovirus serotype 5 (Ad5) vectors are well suited for gene therapy. However, tissue-selective transduction by systemically administered Ad5-based vectors is confounded by viral particle sequestration in the liver. Hexon-modified Ad5 expressing reporter gene under transcriptional control by the immediate/early cytomegalovirus (CMV) or the Roundabout 4 receptor (Robo4) enhancer/promoter was characterized by growth in cell culture, stability in vitro, gene transfer in the presence of human coagulation factor X, and biodistribution in mice. The obtained data demonstrate the utility of the Robo4 promoter in an Ad5 vector context. Substitution of the hypervariable region 7 (HVR7) of the Ad5 hexon with HVR7 from Ad serotype 3 resulted in decreased liver tropism and dramatically altered biodistribution of gene expression. The results of these studies suggest that the combination of liver detargeting using a genetic modification of hexon with an endothelium-specific transcriptional control element produces an additive effect in the improvement of Ad5 biodistribution.

AB - Adenovirus serotype 5 (Ad5) vectors are well suited for gene therapy. However, tissue-selective transduction by systemically administered Ad5-based vectors is confounded by viral particle sequestration in the liver. Hexon-modified Ad5 expressing reporter gene under transcriptional control by the immediate/early cytomegalovirus (CMV) or the Roundabout 4 receptor (Robo4) enhancer/promoter was characterized by growth in cell culture, stability in vitro, gene transfer in the presence of human coagulation factor X, and biodistribution in mice. The obtained data demonstrate the utility of the Robo4 promoter in an Ad5 vector context. Substitution of the hypervariable region 7 (HVR7) of the Ad5 hexon with HVR7 from Ad serotype 3 resulted in decreased liver tropism and dramatically altered biodistribution of gene expression. The results of these studies suggest that the combination of liver detargeting using a genetic modification of hexon with an endothelium-specific transcriptional control element produces an additive effect in the improvement of Ad5 biodistribution.

KW - Adenovirus

KW - Endothelium

KW - Hexon

KW - Roundabout 4 promoter

KW - Targeting

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SN - 0042-6822

VL - 447

SP - 312

EP - 325

JO - Virology

JF - Virology

IS - 1-2

ER -

Retargeting of gene expression using endothelium specific hexon modified adenoviral vector

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Keywords

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