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09:05
MicroRNA-based Regulation of Picornavirus Tropism
Published on: February 6, 2017
p53-dependent antiviral RNA-interference facilitates tumor-selective viral replication
Engin Gürlevik1, Norman Woller, Peter Schache
1Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Carl Neuberg Str. 1, 30625 Hannover, Germany.
Nucleic Acids Research
|May 16, 2009
Summary
This study developed an adenovirus using RNA-interference (RNAi) to target p53-dysfunctional tumors. The novel virus selectively replicates in and lyses these tumors while minimizing liver viral load, offering a promising cancer therapy.
Area of Science:
- Oncolytic virotherapy
- Molecular biology
- Gene therapy
Background:
- RNA-interference (RNAi) enables specific gene silencing.
- Adenoviruses are utilized as vectors for gene therapy and cancer treatment.
- p53 tumor suppressor protein plays a critical role in cell cycle regulation and apoptosis.
Purpose of the Study:
- To engineer an adenovirus for conditional replication in p53-dysfunctional tumor cells.
- To utilize a microRNA-network for p53-selective gene silencing of essential viral genes.
- To evaluate the therapeutic efficacy and safety of the developed oncolytic virus.
Main Methods:
- Development of a replication-conditional adenovirus expressing a p53-selective microRNA-network.
- In vitro and in vivo assessment of viral replication in p53-dysfunctional and normal cells/mice.
- Evaluation of tumor lysis and viral DNA load in liver tissues.
Main Results:
- Antiviral RNAi selectively attenuated viral replication in cells with transcriptionally active p53.
- Both control and engineered viruses replicated equivalently in p53-dysfunctional tumor cells.
- The RNAi-controlled virus efficiently lysed p53-dysfunctional tumors in vitro and in vivo with reduced liver viral DNA load.
Conclusions:
- A broadly applicable adenovirus for selective destruction of p53-dysfunctional tumors was generated.
- Virus-encoded RNAi-networks are efficient and versatile tools to modify viral functions.
- This approach can be applied to transcriptionally regulated DNA-viruses to create specifically replicating vectors for clinical applications.
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