Influence of Coagulation Factor X on In Vitro and In Vivo Gene Delivery by Adenovirus (Ad) 5, Ad35, and Chimeric Ad5/Ad35 Vectors

被引：34

作者：

Greig, Jenny A. ^{[1
]}

Buckley, Suzanne M. K. ^{[2
,3
]}

Waddington, Simon N. ^{[2
,3
]}

Parker, Alan L. ^{[1
]}

Bhella, David ^{[4
]}

Pink, Rebecca ^{[4
]}

Rahim, Ahad A. ^{[2
,3
]}

Morita, Takashi ^{[5
]}

Nicklin, Stuart A. ^{[1
]}

McVey, John H. ^{[6
]}

Baker, Andrew H. ^{[1
]}

机构：

[1] Univ Glasgow, Glasgow Cardiovasc Res Ctr, British Heart Fdn, Glasgow G12 8TA, Lanark, Scotland

[2] Royal Free & Univ Coll Med Sch, Dept Haematol, Haemophilia Ctr, London WC1E 6BT, England

[3] Royal Free & Univ Coll Med Sch, Haemostasis Unit, London WC1E 6BT, England

[4] Univ Glasgow, MRC, Virol Unit, Inst Virol, Glasgow G12 8TA, Lanark, Scotland

[5] Meiji Pharmaceut Univ, Dept Biochem, Tokyo, Japan

[6] Thrombosis Res Inst, London, England

来源：

MOLECULAR THERAPY | 2009年 / 17卷 / 10期

基金：

英国生物技术与生命科学研究理事会;

关键词：

HUMAN CD46-TRANSGENIC MICE; INTRACELLULAR TRAFFICKING; NEUTRALIZING ANTIBODIES; SEROTYPE-35; FIBERS; VACCINE VECTORS; TUMOR-CELLS; CAR-BINDING; SUBGROUP-D; TRANSDUCTION; RECEPTOR;

D O I：

10.1038/mt.2009.152

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

The binding of coagulation factor X (FX) to the hexon of adenovirus (Ad) 5 is pivotal for hepatocyte transduction. However, vectors based on Ad35, a subspecies B Ad, are in development for cancer gene therapy, as Ad35 utilizes CD46 (which is upregulated in many cancers) for transduction. We investigated whether interaction of Ad35 with FX influenced vector tropism using Ad5, Ad35, and Ad5/Ad35 chimeras: Ad5/fiber(f) 35, Ad5/penton(p)35/f35, and Ad35/f5. Surface plasmon resonance (SPR) revealed that Ad35 and Ad35/f5 bound FX with approximately tenfold lower affinities than Ad5 hexon-containing viruses, and electron cryomicroscopy (cryo-EM) demonstrated a direct Ad35 hexon: FX interaction. The presence of physiological levels of FX significantly inhibited transduction of vectors containing Ad35 fibers (Ad5/f35, Ad5/p35/f35, and Ad35) in CD46-positive cells. Vectors were intravenously administered to CD46 transgenic mice in the presence and absence of FX-binding protein (X-bp), resulting in reduced liver accumulation for all vectors. Moreover, Ad5/f35 and Ad5/p35/f35 efficiently accumulated in the lung, whereas Ad5 demonstrated poor lung targeting. Additionally, X-bp significantly reduced lung genome accumulation for Ad5/f35 and Ad5/p35/f35, whereas Ad35 was significantly enhanced. In summary, vectors based on the full Ad35 serotype will be useful vectors for selective gene transfer via CD46 due to a weaker FX interaction compared to Ad5.

引用

页码：1683 / 1691

页数：9

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