Angiotensin II increases gene expression after selective intra-arterial adenovirus delivery in a rabbit model assessed using in vivo SSTR2-based reporter imaging.

Sheela P Singh,Katherine A Dixon,Murali K Ravoori,Sanjay Gupta,Lin Han,Vikas Kundra,Kenneth C Wright,Rajesh Uthamanthil

doi:10.1186/s13550-016-0183-x

Sheela P Singh, Katherine A Dixon + Show 6 more

Open Access

https://doi.org/10.1186/s13550-016-0183-x

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Abstract

BackgroundGene therapy has been hampered by low expression upon in vivo delivery. Using a somatostatin receptor type 2 (SSTR2)-based reporter, we assessed whether angiotensin II (AII) can improve gene expression by adenovirus upon intra-arterial (IA) delivery in a large animal model.MethodsA SSTR2-based reporter that can be imaged by a clinically approved radiopharmaceutical was used to assess gene expression. Eight rabbits bearing VX2 tumors in each thigh were randomly injected IA with adenovirus containing a human SSTR2 (Ad-CMV-HA-SSTR2) gene chimera ± AII or control adenovirus containing green fluorescent protein (Ad-CMV-GFP). Three days later, 111In-octreotide was given IV after computed tomography (CT) imaging using a clinical CT scanner and intravenous contrast. Tumor uptake of 111In-octreotide was evaluated the next day using a clinical gamma camera. Gene expression was normalized to tumor weight and morphology from CT to obtain in vivo biodistribution.ResultsSSTR2-based expression was readily visualized. VX2 tumors infected with Ad-CMV-HA-SSTR2 upon intra-arterial delivery with AII had greater in vivo biodistribution, thus greater gene expression, than those without AII (p < 0.01, n = 6). VX2 tumors infected with Ad-CMV-HA-SSTR2 upon IA delivery had greater biodistribution, thus greater gene expression, than those with the negative control Ad-CMV-GFP (p < 0.02). Similarly, VX2 tumors infected with Ad-CMV-HA-SSTR2 upon IA delivery with AII had greater biodistribution, thus greater gene expression, than those with the negative control Ad-CMV-GFP (p < 0.01).ConclusionsAngiotensin II improves in vivo gene expression by adenovirus upon intra-arterial delivery and thus may improve gene therapy efficacy. In vivo SSTR2-based reporter imaging can be used to compare methodologies for improving gene expression.

Highlights

Gene therapy has been hampered by low expression upon in vivo delivery
We have demonstrated that a combination of anatomic and functional imaging can be used to quantify SSTR2-based gene expression [18,19,20] in small animal models using the FDA-approved radiopharmaceutical 111In-octreotide
Ad-CMV-HA-SSTR2 results in HA-SSTR2 expression in vitro The VX2 tumors are carried as tumor implants and not as cell lines

Summary

Introduction

Gene therapy has been hampered by low expression upon in vivo delivery. Two of the major limitations to gene therapy have been delivery and an inability to monitor exogenous gene expression in vivo. For the former, the vector may be delivered by direct injection into the parenchyma of the tumor or organ of interest, via inhalation, intravenously, or intra-arterially. Arterial delivery may be used to direct the vector to the organ or tumor of interest, when delivery is directed via a catheter to the primary artery feeding the tumor Even with this approach, expression may not be greater than intra-tumoral delivery [1]. Whether pharmacologic manipulation can increase expression upon intra-arterial adenovirus delivery needs exploration

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