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

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.

Nicol CG ，Graham D ，Miller WH ，White SJ ，Smith TA ，Nicklin SA ，Stevenson SC ，Baker AH ... -  《MOLECULAR THERAPY》

Adenovirus serotype 5 fiber shaft influences in vivo gene transfer in mice.

Smith TA ，Idamakanti N ，Rollence ML ，Marshall-Neff J ，Kim J ，Mulgrew K ，Nemerow GR ，Kaleko M ，Stevenson SC ... -  《HUMAN GENE THERAPY》

Reduction of natural adenovirus tropism to the liver by both ablation of fiber-coxsackievirus and adenovirus receptor interaction and use of replaceable short fiber.

Nakamura T ，Sato K ，Hamada H 《-》

Influence of fiber detargeting on adenovirus-mediated innate and adaptive immune activation.

Schoggins JW ，Nociari M ，Philpott N ，Falck-Pedersen E ... -  《-》

Simultaneous CAR- and alpha V integrin-binding ablation fails to reduce Ad5 liver tropism.

Martin K ，Brie A ，Saulnier P ，Perricaudet M ，Yeh P ，Vigne E ... -  《MOLECULAR THERAPY》