Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Exp Med. May 20, 2016; 6(2): 37-54
Published online May 20, 2016. doi: 10.5493/wjem.v6.i2.37
MicroRNA-regulated viral vectors for gene therapy
Anja Geisler, Henry Fechner
Anja Geisler, Henry Fechner, Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany
Author contributions: The authors equally contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the final version.
Supported by The Deutsche Forschungsgemeinschaft, Nos. FE785/2-2 and FE785/4-1; and the Bundesministerium für Bildung und Entwicklung, No. 031A331.
Conflict-of-interest statement: The authors declare no conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Henry Fechner, DVM, Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Gustav-Meyer-Allee 25, 13355 Berlin, Germany.
Telephone: +49-30-31472181 Fax: +49-30-31427502
Received: August 27, 2015
Peer-review started: August 31, 2015
First decision: October 27, 2015
Revised: March 2, 2016
Accepted: March 17, 2016
Article in press: March 18, 2016
Published online: May 20, 2016

Safe and effective gene therapy approaches require targeted tissue-specific transfer of a therapeutic transgene. Besides traditional approaches, such as transcriptional and transductional targeting, microRNA-dependent post-transcriptional suppression of transgene expression has been emerging as powerful new technology to increase the specificity of vector-mediated transgene expression. MicroRNAs are small non-coding RNAs and often expressed in a tissue-, lineage-, activation- or differentiation-specific pattern. They typically regulate gene expression by binding to imperfectly complementary sequences in the 3’ untranslated region (UTR) of the mRNA. To control exogenous transgene expression, tandem repeats of artificial microRNA target sites are usually incorporated into the 3’ UTR of the transgene expression cassette, leading to subsequent degradation of transgene mRNA in cells expressing the corresponding microRNA. This targeting strategy, first shown for lentiviral vectors in antigen presenting cells, has now been used for tissue-specific expression of vector-encoded therapeutic transgenes, to reduce immune response against the transgene, to control virus tropism for oncolytic virotherapy, to increase safety of live attenuated virus vaccines and to identify and select cell subsets for pluripotent stem cell therapies, respectively. This review provides an introduction into the technical mechanism underlying microRNA-regulation, highlights new developments in this field and gives an overview of applications of microRNA-regulated viral vectors for cardiac, suicide gene cancer and hematopoietic stem cell therapy, as well as for treatment of neurological and eye diseases.

Keywords: MicroRNA, MicroRNA regulation, MicroRNA target sites, Viral vectors, Adeno-associated virus, RNA interference, Gene therapy, Vector targeting

Core tip: Post-transcriptional microRNA-induced suppression of gene expression is a simple new, highly efficient technology to restrict transgene expression to a specific tissue. It is based on the insertion of a target sequence for a cell-specifically expressed microRNA, typically into the 3’ untranslated region of a transgene expression cassette. MicroRNA-induced regulation can result in an up to 100-fold reduction of transgene expression in tissues where expression is not desired. This targeting strategy can be used in combination with other targeting strategies to further improve vector specificity for gene therapeutic approaches.