[Frontiers in Bioscience 16, 2389-2401, June 1, 2011]

MicroRNA-regulated transgene expression systems for gene therapy and virotherapy

Fuminori Sakurai1,2, Kazufumi Katayama1,2, Hiroyuki Mizuguchi1,2

1Department of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan, 2Laboratory of Stem Cell Regulation, National Institute of Biomedical Innovation, Osaka, Japan

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Mechanism of microRNA-mediated post-transcriptional gene silencing
4. Factors to be considered for construction of microRNA-regulated transgene expression systems
5. Application of microRNA-regulated transgene expression systems
5.1. Regulation of suicide gene expression
5.2. Regulation of DNA virus replication
5.3. Regulation of RNA virus replication
5.4. Regulation of immune responses against transgene products
5.5. Other applications
6. Concluding remarks
7. Acknowledgements
8. References

1. ABSTRACT

For safe and effective gene therapy, targeted tissue-restricted transgene expression is desirable. Various methods have been developed to achieve such expression, including the use of tissue-specific promoters. In addition to these approaches, a new system which can regulate transgene expression, including viral gene expression, by exploiting microRNAs (miRNAs) has recently been developed. miRNAs are approximately 22-nucleotide (nt)-long non-coding RNAs that translationally suppress or catalytically degrade target mRNA through binding to imperfectly complementary sequences in the 3'-untranslated region (UTR). In miRNA-regulated transgene expression systems, tandem copies of sequences perfectly complementary to the miRNAs are usually incorporated into the 3'-UTR of the transgene expression cassette, leading to the suppression of transgene expression in cells expressing the corresponding miRNAs. miRNA-mediated regulation of transgene expression was first demonstrated for lentivirus vectors, and subsequently this technology was applied to replication-incompetent adenovirus vectors, tumor-specific oncolytic viruses for cancer therapy, and recombinant live attenuated viruses for vaccine therapy. The aim of this review is to highlight the applications of miRNA-regulated transgene expression systems for gene therapy and virotherapy.