The application of multiple miRNA response elements enables oncolytic adenoviruses to possess specificity to glioma cells

•The levels of miR-124, miR-128, miR-146b and miR-218 are reduced in glioma.•Their MREs can regulate the expression of exogenous gene in glioma cells.•These MREs retarget adenovirus to glioma cells.•The adenoviruses regulated by the MREs suppress the growth of glioma in mice and have no toxicity to normal brain and liver.

Adenovirus-mediated virotherapy is one of the promising therapeutic approaches for glioma treatment. However, its replication efficiency and specificity still failed to meet the requirements for clinical treatment. To improve the anti-tumor activity and specificity of oncolytic adenoviruses (OA), we applied multiple miRNA response elements (MREs) of miR-124, miR-128, miR-146b and miR-218, whose expressions were downregulated in glioma cells, to enable OA to be specific to glioma. Adenoviral E1A protein regulated by these 4 MREs (OA-4MREs) was shown to be highly expressed in glioma cells, but not in normal cells. The selective E1A expression led to glioma-specific replication and cytotoxicity of OA-4MREs. Animal experiments also showed that OA-4MREs exhibited improved anti-tumor activities for both subcutaneous and intracranial glioma xenografts, without significant toxicity to normal brain and liver tissues. Collectively, we demonstrated that oncolytic adenovirus, whose replication was regulated by MREs, may be promising biological agents for glioma treatment.