A conditionally replicating adenovirus targeted to tumor cells through activated RAS/P-MAPK-selective mRNA stabilization

Atique Ahmed, Jill Thompson, Lisa Emiliusen, Stephen Murphy, R. Daniel Beauchamp, Kaori Suzuki, Ramon Alemany, Kevin Harrington, Richard G. Vile

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

The expression of various proteins associated with rapid responses to inflammation and/or proliferation can be controlled at the level of mRNA stability. Because tumor cells continually recapitulate intracellular programs of proliferation, we have used tumor cell-selective stabilization of mRNA as a means to control therapeutic gene expression. We describe an adenoviral vector that is conditionally replication competent in which expression of the essential adenoviral early region 1A (E1A) gene is regulated by ligation to the 3′ untranslated region (UTR) of PTGS2 (also known as COX2), the gene encoding prostaglandin-endoperoxide synthase 2, allowing activated RAS/P-MAPK-specific stabilization of its mRNA. Induction of activated RAS supports replication, whereas matched cells in which activated RAS/P-MAPK is not expressed are very poor substrates for viral replication both in vitro and in vivo. Further tumor-targeting strategies will also be required to prevent viral replication at extratumoral sites where PTGS2 is normally induced. Many different genes contain 3′ UTRs that control selective mRNA stability under different physiological, pathological and tumor-associated conditions. Therefore, generating tumor selectivity at the level of mRNA stability is a strategy with broad potential applicability in vector design.

Original languageEnglish (US)
Pages (from-to)771-777
Number of pages7
JournalNature biotechnology
Volume21
Issue number7
DOIs
StatePublished - Jul 1 2003

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

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    Ahmed, A., Thompson, J., Emiliusen, L., Murphy, S., Beauchamp, R. D., Suzuki, K., Alemany, R., Harrington, K., & Vile, R. G. (2003). A conditionally replicating adenovirus targeted to tumor cells through activated RAS/P-MAPK-selective mRNA stabilization. Nature biotechnology, 21(7), 771-777. https://doi.org/10.1038/nbt835