Tropism-modification strategies for targeted gene delivery using adenoviral vectors

Coughlan, L., Alba, R., Parker, A.L., Bradshaw, A.C. , Mcneish, I.A. , Nicklin, S. and Baker, A. (2010) Tropism-modification strategies for targeted gene delivery using adenoviral vectors. Viruses, 2(10), pp. 2290-2355. (doi: 10.3390/v2102290) (PMID:21994621) (PMCID:PMC3185574)

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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 efficiency and clinical potential of Ad5-based therapeutics. To date, various approaches to retargeting adenoviruses (Ad) have been described. These include genetic modification strategies to incorporate peptide ligands (within fiber knob domain, fiber shaft, penton base, pIX or hexon), pseudotyping of capsid proteins to include whole fiber substitutions or fiber knob chimeras, pseudotyping with non-human Ad species or with capsid proteins derived from other viral families, hexon hypervariable region (HVR) substitutions and adapter-based conjugation/crosslinking of scFv, growth factors or monoclonal antibodies directed against surface-expressed target antigens. In order to maximize retargeting, strategies which permit detargeting from undesirable interactions between the Ad capsid and components of the circulatory system (e.g. coagulation factors, erythrocytes, pre-existing neutralizing antibodies), can be employed simultaneously. Detargeting can be achieved by genetic ablation of native receptor-binding determinants, ablation of “bridging interactions” such as those which occur between the hexon of Ad5 and coagulation factor X (FX), or alternatively, through the use of polymer-coated “stealth” vectors which avoid these interactions. Simultaneous retargeting and detargeting can be achieved by combining multiple genetic and/or chemical modifications.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Baker, Professor Andrew and Alba, Dr Raul and Nicklin, Professor Stuart and Bradshaw, Dr Angela and Parker, Dr Alan and Coughlan, Dr Lynda and Mcneish, Professor Iain
Authors: Coughlan, L., Alba, R., Parker, A.L., Bradshaw, A.C., Mcneish, I.A., Nicklin, S., and Baker, A.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Viruses
ISSN (Online):1999-4915
Published Online:13 October 2010
Copyright Holders:Copyright © 2010 The Authors
First Published:First published Viruses 2(10):2290-2355
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
461921Development of efficient disease-regulated expression cassettes for gene therapy using microRNA targeting sequencesStuart NicklinBiotechnology and Biological Sciences Research Council (BBSRC)BB/F006667/1Institute of Cardiovascular and Medical Sciences