PLoS ONE (Jan 2013)

Anti-tumor activity of a miR-199-dependent oncolytic adenovirus.

  • Elisa Callegari,
  • Bahaeldin K Elamin,
  • Lucilla D'Abundo,
  • Simonetta Falzoni,
  • Giovanna Donvito,
  • Farzaneh Moshiri,
  • Maddalena Milazzo,
  • Giuseppe Altavilla,
  • Luciano Giacomelli,
  • Francesca Fornari,
  • Akseli Hemminki,
  • Francesco Di Virgilio,
  • Laura Gramantieri,
  • Massimo Negrini,
  • Silvia Sabbioni

DOI
https://doi.org/10.1371/journal.pone.0073964
Journal volume & issue
Vol. 8, no. 9
p. e73964

Abstract

Read online

The down-regulation of miR-199 occurs in nearly all primary hepatocellular carcinomas (HCCs) and HCC cell lines in comparison with normal liver. We exploited this miR-199 differential expression to develop a conditionally replication-competent oncolytic adenovirus, Ad-199T, and achieve tumor-specific viral expression and replication. To this aim, we introduced four copies of miR-199 target sites within the 3' UTR of E1A gene, essential for viral replication. As consequence, E1A expression from Ad-199T virus was tightly regulated both at RNA and protein levels in HCC derived cell lines, and replication controlled by the level of miR-199 expression. Various approaches were used to asses in vivo properties of Ad-199T. Ad-199T replication was inhibited in normal, miR-199 positive, liver parenchyma, thus resulting in reduced hepatotoxicity. Conversely, the intrahepatic delivery of Ad-199T in newborn mice led to virus replication and fast removal of implanted HepG2 liver cancer cells. The ability of Ad-199T to control tumor growth was also shown in a subcutaneous xenograft model in nude mice and in HCCs arising in immune-competent mice. In summary, we developed a novel oncolytic adenovirus, Ad-199T, which could demonstrate a therapeutic potential against liver cancer without causing significant hepatotoxicity.