Genetically modified ZIKA virus as a microRNA-sensitive oncolytic virus against central nervous system tumors
Gabriela Machado Novaes, Caroline Lima, Carla Longo, Pedro Henrique Machado, Thaïs Peron da Silva, Giovanna Gonçalves de Oliveira Olberg, Diego Grando Módolo, Márcia Cristina Leite Pereira, Tiago G. Santos, Mayana Zatz, David Lagares, Marcelo De Franco, Paulo Lee Ho, Harry Bulstrode, Oswaldo Keith Okamoto, Carolini Kaid
Abstract
Here we introduce a first-in-class microRNA-sensitive oncolytic Zika virus (ZIKV) for virotherapy application against central nervous system (CNS) tumors. The described methodology produced two synthetic modified ZIKV strains that are safe in normal cells, including neural stem cells, while preserving brain tropism and oncolytic effects in tumor cells. The microRNA-sensitive ZIKV introduces genetic modifications in two different virus sites: first, in the established 3'UTR region, and secondly, in the ZIKV protein coding sequence, demonstrating for the first time that the miRNA inhibition systems can be functional outside the UTR RNA sites. The total tumor remission in mice bearing human CNS tumors, including metastatic tumor growth, after intraventricular and systemic modified ZIKV administration, confirms the promise of this virotherapy as a novel agent against brain tumors-highly deadly diseases in urgent need of effective advanced therapies.