A novel capsid-modified oncolytic recombinant adenovirus type 5 for tumor-targeting gene therapy by intravenous route.

Zhen Wang,Zixuan Wang,Baoming Wang,Xiao Feng,Bin Yu,Lizheng Wang,Haihong Zhang,Jiaxin Wu,Hui Wu,Wei Kong,Jingyi Yan,Xianghui Yu

doi:10.18632/oncotarget.10075

Zhen Wang, Zixuan Wang + Show 10 more

Open Access

https://doi.org/10.18632/oncotarget.10075

Copy DOI

Journal: Oncotarget	Publication Date: Jun 15, 2016
Citations: 16	License type: cc-by

Affiliation: Jilin University

Abstract

Oncolytic adenovirus (Ad)-vectored gene therapy is a promising strategy for cancer treatment. However, the lack of cancer cell selectivity or tumor tissue specificity of Ads limits their clinical application by intravenous (IV) injection. In this paper, a novel recombinant Ad5 vector was constructed carrying the capsid protein IX modified by the tumor necrosis factor related apoptosis-inducing ligand (TRAIL), which targets tumor cells bearing high levels of its receptor far above those of normal cells. Specific association of the Ad virion with TRAIL was achieved using synthetic leucine zipper-like dimerization domains (zippers). Analysis of the chemical properties of the modified recombinant Ad (rAd5pz-zTRAIL-RFP) showed that the TRAIL protein was present on the surface of purified virus particles, and it could induce apoptosis of infected cancer cells prior to expression of foreign genes. We also constructed a novel modified recombinant oncolytic Ad (rAd5pz-zTRAIL-RFP-SΔ24E1a) which showed significantly enhanced anti-tumor effects both in vitro and in vivo by linkage of TRAIL to the viral capsid. Moreover, rAd5pz-zTRAIL-RFP-SΔ24E1a showed significantly improved tumor tissue targeting and reduced liver tropism when IV injected in vivo. Thus, we successfully obtained new oncolytic Ad5 gene therapy vectors with enhanced targeting and efficacy, providing a platform for further clinical application of Ad vectors for cancer treatment.

Highlights

Viruses are widely used to develop replicative vector therapies for cancer [1, 2]
Construction of an Ad vector coupled with tumor necrosis factor related apoptosis-inducing ligand (TRAIL) using leucine zipper heterodimers The TRAIL trimer has demonstrated potent antitumor activity in cancer models based on tumor cell lines and primary tumor samples
We used two heterodimeric zipper pairs (E·E34/R·R34) [31], wherein one zipper domain was genetically incorporated onto the C-terminus of the pIX, and its counterpart was fused to the N-terminus of TRAIL (Figure 1B)

Summary

Introduction

Viruses are widely used to develop replicative vector therapies for cancer (virotherapy and oncolysis) [1, 2]. Oncolytic adenoviruses (Ads), known as conditionally replicating Ads (CRAds), are among the most popular viruses used for cancer gene therapy [3,4,5]. Their main advantage is selective viral replication in tumor cells but not in normal cells. A practical explanation for this result is the retention of greater than 80% of the systemically injected Ad in the liver [10], because the binding of Ad5 with FX through FX Gla domain and the Hexon HVRs can deliver adenovirus to hepatocytes existing in the bloodstream in vivo [11,12,13] Such liver tropism poses a problem when using Ad vectors targeting tumors in other tissues. Since pIX is exposed on the surface of the virion, its mutants have been used as a platform for ligand insertion at its C terminus, with the aim of developing cell-targeted vectors for gene therapy [14, 15]

Methods

Results

Conclusion