Methoxyethyl-modified intercellular adhesion molecule-1 antisense phosphorothiateoligonucleotides inhibit allograft rejection, ischemic-reperfusion injury, and cyclosporin-induced nephrotoxicity

Wenhau Chen, Robert M. Langer, Slawa Janczewska, Lucrezia Furian, Richard Geary, Xuimei Qu, Mouer Wang, Regina Verani, Tom Condon, Kim Stecker, C. Frank Bennett, Stanislaw M. Stepkowski

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Background. The addition of phosphorothioate (PS) groups to natural phosphodiester (PD) antisense oligodeoxynucleotides (oligo) prevents their in vivo hydrolysis by nucleases allowing an RNase-dependent elimination of targeted mRNA. To further improve oligo function 2′-methoxyethyl (ME) groups were attached to selected nucleotides at the 3′-end because ME groups block RNase activity. Methods/Results. ME modification of PS- or PD/PS-oligo targeting human intracellular adhesion molecule (ICAM)-1 mRNA significantly increased the degree and duration of the in vitro inhibitory effects without compromising selectivity and specificity. A 7-day intravenous or oral therapy with rat ME/PS-modified ICAM-1 antisense oligo extended the survivals of kidney allografts. In addition, ME/PS-modified ICAM-1 antisense oligo reduced ischemic-reperfusion injury in kidneys, as measured by glomerular filtration rate, creatinine levels, and infiltration with leukocytes. Finally, a 14-day treatment with cyclosporine (CsA)-induced nephrotoxicity in syngeneic kidney transplants correlated with both increased ICAM-1 protein expression and infiltration with leukocytes. Graft perfusion and treatment of recipients with ICAM-1 antisense ME/PS-oligo alleviated the nephrotoxic effect and decreased ICAM-1 expression and leukocyte infiltration. Conclusions. ME/PS-modified ICAM-1 antisense oligo is very effective in inhibiting the ICAM-1-dependent mechanism of graft infiltration and tissue damage involved in allograft rejection, ischemic-reperfusion injury, and CsA-induced nephrotoxicity.

Original languageEnglish (US)
Pages (from-to)401-408
Number of pages8
JournalTransplantation
Volume79
Issue number4
DOIs
StatePublished - Feb 27 2005

Keywords

  • Antisense oligonucleotides
  • ICAM-1
  • Immunosuppression
  • Ischemia-reperfusion injury
  • Kidney
  • Transplantation

ASJC Scopus subject areas

  • Transplantation

Fingerprint Dive into the research topics of 'Methoxyethyl-modified intercellular adhesion molecule-1 antisense phosphorothiateoligonucleotides inhibit allograft rejection, ischemic-reperfusion injury, and cyclosporin-induced nephrotoxicity'. Together they form a unique fingerprint.

Cite this