Premium
Persistent interferon transgene expression by RNA interference‐mediated silencing of interferon receptors
Author(s) -
Takahashi Yuki,
Vikman Elin,
Nishikawa Makiya,
Ando Mitsuru,
Watanabe Yoshihiko,
Takakura Yoshinobu
Publication year - 2010
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1493
Subject(s) - gene silencing , transgene , rna interference , transfection , biology , small interfering rna , interferon , genetic enhancement , receptor , microbiology and biotechnology , small hairpin rna , gene , cancer research , rna , virology , genetics
Background The in vivo half‐life of interferons (IFNs) is very short, and its extension would produce a better therapeutic outcome in IFN‐based therapy. Delivery of IFN genes is one solution for providing a sustained supply. IFNs have a variety of functions, including the suppression of transgene expression, through interaction with IFN receptors (IFNRs). This suppression could prevent IFNs from being expressed from vectors delivered. Silencing the expression of IFNAR and IFNGR, the receptors for type I and II IFNs, respectively, in cells expressing IFNs may prolong transgene expression of IFNs. Methods Mouse melanoma B16‐BL6 cells or mouse liver were selected as a site expressing IFNs (not a target for IFN gene therapy) and IFN‐expressing plasmid DNA was delivered with or without small interfering RNA (siRNA) targeting IFNRs. Results Transfection of B16‐BL6 cells with siRNA targeting IFNAR1 subunit (IFNAR1) resulted in the reduced expression of IFNAR on the cell surface. This silencing significantly increased the IFN‐β production in cells that were transfected with IFN‐β‐expressing plasmid DNA. Similar results were obtained with the combination of IFN‐γ and IFNGR. Co‐injection of IFN‐β‐expressing plasmid DNA with siRNA targeting IFNAR1 into mice resulted in sustained plasma concentration of IFN‐β. Conclusions These results provide experimental evidence that the RNAi‐mediated silencing of IFNRs in cells expressing IFN, such as hepatocytes, is an effective approach for improving transgene expression of IFNs when their therapeutic target comprises cells other than those expressing IFNs. Copyright © 2010 John Wiley & Sons, Ltd.