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Tumor-specific adenoviral gene therapy: transcriptional repression of gene expression by utilizing p53-signal

Florian Kühnel1, Lars Zender, Thomas Wirth

  • 1Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Carl Neuberg Str. 1, 30625 Hannover, Germany.

Cancer Gene Therapy
|December 19, 2003
PubMed

Insights

This study developed a tumor-specific gene therapy using adenoviral vectors. It leverages p53 pathway activation to control gene expression, achieving over 99% repression in normal cells for enhanced safety.

Area of Science:

  • Oncolytic Virotherapy
  • Molecular Biology
  • Gene Therapy

Background:

  • p53 tumor suppressor protein plays a critical role in cellular response to DNA damage.
  • Adenoviral vectors are widely used in gene therapy but lack tumor specificity.
  • Targeted gene expression is crucial for effective and safe cancer gene therapy.

Purpose of the Study:

  • To develop a novel adenoviral gene therapy strategy for tumor-specific gene expression.
  • To identify effective transcriptional repressors for controlling gene expression in a p53-dependent manner.
  • To enhance tumor selectivity of adenoviral vectors by utilizing the p53 pathway.

Main Methods:

  • Construction of CMV-driven adenoviral vectors (CMVgal) with GAL4-binding sites.
  • Investigation of 11 GAL4-DNA binding domain (DBD) fusion proteins for transcriptional repression.
  • Utilizing a p53-dependent promoter to control the expression of the GAL4-KRAB-A repressor.
  • Employing double-recombinant adenoviral vectors (Ad-RGCdR) for gene delivery.

Main Results:

  • GAL4-KRAB-A demonstrated potent repression of CMVgal activity in p53 wild-type cells.
  • Adenoviral vector Ad-RGCdR showed p53-dependent gene expression, higher in p53 mutant cells.
  • Preactivation of p53 signaling via chemotherapy enhanced repression in wild-type cells (>99%).
  • Achieved significant tumor-specific gene expression control by leveraging p53 signaling.

Conclusions:

  • Controlled gene expression via transcriptional repression is a viable strategy for tumor-specific adenoviral gene therapy.
  • The p53 pathway can be effectively utilized to enhance the safety and specificity of adenoviral gene therapy.
  • The developed Ad-RGCdR vector with GAL4-KRAB-A offers a promising tool for targeting cancers with functional p53 signaling.

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