Tropism-Modification Strategies for Targeted Gene Delivery Using Adenoviral Vectors 英文参考文献.docVIP

Viruses 2010, 2, 2290-2355; doi:10.3390/v2102290 OPEN ACCESS viruses ISSN 1999-4915 /journal/viruses Review Tropism-Modification Strategies for Targeted Gene Delivery Using Adenoviral Vectors Lynda Coughlan 1, Raul Alba 1, Alan L. Parker 1, Angela C. Bradshaw 1, Iain A. McNeish 2, Stuart A. Nicklin 1 and Andrew H. Baker 1,* 1 Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK; E-Mails: Lynda.Coughlan @glasgow.ac.uk (L.C.), Raul.Alba@glasgow.ac.uk (R.A.), Alan.Parker@glasgow.ac.uk (A.L.P.); Angela.Bradshaw@glasgow.ac.uk (A.C.B.); Stuart.Nicklin@glasgow.ac.uk (S.A.N.) 2 Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK; E-Mail: i.a.mcneish@qmul.ac.uk * Author to whom correspondence should be addressed; E-Mail: Andrew.H.Baker@glasgow.ac.uk; Tel.: +44 141 330 1977; Fax: +44 141 330 6997. Received: 2 September 2010 / Accepted: 7 October 2010 / Published: 13 October 2010 Abstract: Achieving high efficiency, targeted gene delivery with adenoviral vectors is a long-standing goal in the field of clinical gene therapy. To achieve this, platform vectors must combine efficient retargeting strategies with detargeting modifications to ablate native receptor binding (i.e. CAR/integrins/heparan sulfate proteoglycans) and “bridging” interactions. “Bridging” interactions refer to coagulation factor binding, namely coagulation factor X (FX), which bridges hepatocyte transduction in vivo through engagement with surface expressed heparan sulfate proteoglycans (HSPGs). These interactions can contribute to the off-target sequestration of Ad5 in the liver and its characteristic dose-limiting hepatotoxicity, thereby significantly limiting the in vivo targeting effic