Methoxyethyl-modified intercellular adhesion molecule-1 antisense phosphorothiateoligonucleotides inhibit allograft rejection, ischemic-reperfusion injury, and cyclosporine-induced nephrotoxicity.
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.
Chen
Wenhau
W
Division of Immunology and Organ Transplantation, The University of Texas Medical School-Houston, 6431 Fannin, Houston, TX 77030, USA.
Langer
Robert M
RM
Janczewska
Slawa
S
Furian
Lucrezia
L
Geary
Richard
R
Qu
Xuimei
X
Wang
Mouer
M
Verani
Regina
R
Condon
Tom
T
Stecker
Kim
K
Bennett
C Frank
CF
Stepkowski
Stanislaw M
SM
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
D007166:Immunosuppressive Agents; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine