Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1

Dan Peer, Pengcheng Zhu, Christopher V. Carman, Judy Lieberman, Motomu Shimaoka

Research output: Contribution to journalArticle

218 Scopus citations

Abstract

Silencing gene expression by RNAi is a powerful method for exploring gene function and validating drug targets and potentially for therapy. Lymphocytes and other primary blood cells are resistant to lipid-based transfection in vitro and are difficult to target in vivo. We show here that antibody-protamine fusion proteins targeting the human integrin lymphocyte function-associated antigen-1 (LFA-1) efficiently deliver siRNAs and specifically induce silencing in primary lymphocytes, monocytes, and dendritic cells. Moreover, a fusion protein constructed from an antibody that preferentially recognizes activation-dependent conformational changes in LFA-1 selectively targets activated leukocytes and can be used to suppress gene expression and cell proliferation only in activated lymphocytes. The siRNA-fusion protein complexes do not cause lymphocyte activation or induce IFN responses. K562 cells expressing latent WT or constitutively activated LFA-1 engrafted in the lungs of SCID mice are selectively targeted by intravenously injected fusion protein-siRNA complexes, demonstrating the potential in vivo applicability of LFA-1-directed siRNA delivery.

Original languageEnglish (US)
Pages (from-to)4095-4100
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number10
DOIs
StatePublished - Mar 6 2007

Keywords

  • Affinity up-regulation
  • AL-57 and TS1/22
  • Antiinflammation
  • Cell adhesion molecule
  • Drug delivery

ASJC Scopus subject areas

  • Genetics
  • General

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