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Double-detargeted oncolytic adenovirus shows replication arrest in liver cells and retains neuroendocrine cell

Justyna Leja1, Berith Nilsson, Di Yu

  • 1Division of Clinical Immunology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Plos One
|January 30, 2010
PubMed
Abstract

Insights

Engineered oncolytic adenovirus (Ad5) uses a liver-specific microRNA (miR122) to control E1A expression, preventing liver toxicity in neuroendocrine tumor treatment. This dual regulation enhances safety without compromising tumor cell killing efficacy.

Area of Science:

  • Oncolytic virotherapy
  • Gene therapy
  • Molecular biology

Background:

  • Oncolytic serotype 5 adenovirus (Ad5) with chromogranin-A (CgA) promoter-controlled E1A expression (Ad[CgA-E1A]) was developed for neuroendocrine tumor treatment.
  • Repressing viral replication in hepatocytes is crucial to mitigate adenovirus-related liver toxicity, especially for carcinoid tumors metastasizing to the liver.
  • MicroRNA (miRNA)-based regulation offers a complementary approach to promoter control for managing E1A expression.

Purpose of the Study:

  • To investigate miRNA-based regulation of E1A expression in oncolytic adenovirus as a safety mechanism.
  • To enhance the tumor-targeting specificity of Ad[CgA-E1A] by incorporating liver-specific miRNA targeting.
  • To evaluate the efficacy and safety of a modified adenovirus in preclinical models.

Main Methods:

  • Construction of Ad[CgA-E1A-miR122], featuring E1A expression controlled by both the CgA promoter and six tandem repeats of the miR122 target sequence.
  • Comparison of Ad[CgA-E1A-miR122] with Ad[CgA-E1A] in normal hepatocytes and carcinoid tumor cells.
  • Assessment of viral replication and toxicity in vitro and in vivo following intravenous injections in mice.

Main Results:

  • Ad[CgA-E1A-miR122] demonstrated suppressed E1A expression and arrested replication in normal hepatocytes.
  • Both Ad[CgA-E1A] and Ad[CgA-E1A-miR122] exhibited equivalent efficacy in killing carcinoid cells.
  • Intravenous injections of Ad[CgA-E1A] induced liver toxicity in mice, whereas Ad[CgA-E1A-miR122] did not.
  • A miR122-detargeted adenovirus with a wild-type E1A promoter showed reduced hepatic replication compared to wild-type Ad5, but less so than the miR122-detargeted Ad[CgA-E1A].

Conclusions:

  • Combining transcriptional (promoter) and post-transcriptional (miRNA targeting) regulation provides enhanced control over adenovirus replication.
  • This dual-regulation strategy may enable the use of higher oncolytic adenovirus doses for effective tumor treatment.
  • The developed Ad[CgA-E1A-miR122] shows potential for safer and more effective treatment of neuroendocrine tumors by minimizing liver toxicity.

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