Effect of adenovirus serotype 5 fiber and penton modifications on in vivo tropism in rats

Nicol, C., Graham, D., Miller, W., White, S., Smith, T., Nicklin, S., Stevenson, S. and Baker, A. (2004) Effect of adenovirus serotype 5 fiber and penton modifications on in vivo tropism in rats. Molecular Therapy, 10(2), pp. 344-354. (doi: 10.1016/j.ymthe.2004.05.020)

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Abstract

Sequestration of adenovirus serotype 5 (Ad5) in liver restricts its use for gene delivery to other target sites in vivo. To date, no studies have systematically assessed the impact of genetic capsid modifications on in vivo tropism in rats, an important preclinical model for many disease types. We evaluated a panel of Ad5 vectors with capsid mutations or pseudotyped with the short fiber from serotype 41 (Ad41s) for infectivity in Wistar Kyoto rats in vitro and systemically in vivo. In vitro studies demonstrated that both coxsackie and adenovirus receptor (CAR) and heparan sulfate proteoglycan (HSPG) binding were predominant predictors of Ad5 tropism. In vivo, neither CAR nor integrin mutations alone affected liver transduction. The HSPG-binding mutation alone moderately reduced rat liver transgene levels by 2-fold (P < 0.05). This was further substantially decreased by additional mutation of CAR binding (95-fold). Combining CAR and integrin mutations reduced transgene levels by >99% (509-fold, P < 0.01), an effect not observed in parallel experiments in mice and highly variable when studied further in an additional two strains of rat. Ad41s mediated very low liver transduction (58-fold lower than AdCTL). Moreover, CAR-binding mutants (KO1-containing) or pseudotyping 41s eliminated hemagglutination of rat and human red blood cells in vitro. This highlights some important potential species and strain differences dictating Ad5 tropism in vivo and identifies vectors that are substantially detargeted from rat liver in vivo.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nicklin, Professor Stuart and Baker, Professor Andrew
Authors: Nicol, C., Graham, D., Miller, W., White, S., Smith, T., Nicklin, S., Stevenson, S., and Baker, A.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Molecular Therapy
Publisher:Nature Publishing Group
ISSN:1525-0016
ISSN (Online):1525-0024

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