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Recent studies have demonstrated the importance of coagulation factor X (FX) in adenovirus (Ad) serotype 5-mediated liver transduction in vivo. FX binds to the adenovirus hexon hypervariable regions (HVRs). Here, we perform a systematic analysis of FX binding to Ad5 HVRs 5 and 7, identifying domains and amino acids critical for this interaction. We(More)
Last-generation adenovirus vectors, also called helper-dependent or gutless adenovirus, are very attractive for gene therapy because the associated in vivo immune response is highly reduced compared to first- and second-generation adenovirus vectors, while maintaining high transduction efficiency and tropism. Nowadays, gutless adenovirus is administered in(More)
A major limitation for adenoviral transduction in vivo is the profound liver tropism of adenovirus type 5 (Ad5). Recently, we demonstrated that coagulation factor X (FX) binds to Ad5-hexon protein at high affinity to mediate hepatocyte transduction after intravascular delivery. We developed novel genetically FX-binding ablated Ad5 vectors with lower liver(More)
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"(More)
The immunogenicity and cytotoxicity associated with early generations of adenoviral vectors provided a strong incentive for the development of helper-dependent adenovirus, a last generation of adenoviral vectors that is devoid of all viral coding sequences. These vectors have shown to mediate longer high-level transgene expression in vivo with reduced(More)
Serotonin is produced by pulmonary arterial endothelial cells (PAEC) via tryptophan hydroxylase-1 (Tph1). Pathologically, serotonin acts on underlying pulmonary arterial cells, contributing to vascular remodeling associated with pulmonary arterial hypertension (PAH). The effects of hypoxia on PAEC-Tph1 activity are unknown. We investigated the potential of(More)
The use of adenovirus serotype 5 (Ad5) vectors in the clinical setting is severely hampered by the profound liver tropism observed after intravascular delivery coupled with the pronounced inflammatory and innate immune response elicited by these vectors. Liver transduction by circulating Ad5 virions is mediated by a high-affinity interaction between the(More)
Endovenously administered oncolytic viruses extravasate and penetrate poorly into tumors. iRGD is a cyclic peptide that enhances tumor penetration when conjugated or coadministered with different types of molecules such as drugs, nanoparticles or phages. iRGD-mediated tumor penetration occurs in three steps: binding to αv-integrins on tumor vasculature or(More)
BACKGROUND Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions,(More)
Current strategies to amplify helper-dependent adenovirus, based on excision of the packaging signal, do not routinely reduce helper adenovirus contamination below 1%. Here, we have tested if reducing the efficiency of the packaging process of the helper adenovirus could impair its packaging without affecting helper-dependent adenovirus production.(More)