title: Methoxyethyl-modified intercellular adhesion molecule-1 antisense phosphorothiateoligonucleotides inhibit allograft rejection, ischemic-reperfusion injury, and cyclosporine-induced nephrotoxicity.
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.
  
  
  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.
authors.affiliation: Division of Immunology and Organ Transplantation, The University of Texas Medical School-Houston, 6431 Fannin, Houston, TX 77030, USA.
authors.forename: Wenhau
authors.initials: W
authors.lastname: Chen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Langer
authors.forename: Slawa
authors.initials: S
authors.lastname: Janczewska
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Furian
authors.forename: Richard
authors.initials: R
authors.lastname: Geary
authors.forename: Xuimei
authors.initials: X
authors.lastname: Qu
authors.forename: Mouer
authors.initials: M
authors.lastname: Wang
authors.forename: Regina
authors.initials: R
authors.lastname: Verani
authors.forename: Tom
authors.initials: T
authors.lastname: Condon
authors.forename: Kim
authors.initials: K
authors.lastname: Stecker
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Stanislaw M
authors.initials: SM
authors.lastname: Stepkowski
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016572:Cyclosporine / Q000633:toxicity*; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D007668:Kidney / Q000187:drug effects*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000517:prevention & control*; D013873:Thionucleotides / Q000494:pharmacology*; D014184:Transplantation, Homologous
chemical_list: D007166:Immunosuppressive Agents; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine