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 oligode-oxynucleotides (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- I antisense oligo extended the survivals of kidney allografts. In addition, ME/PS-modified ICAM- I 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- I 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- I expression and leukocyte infiltration. Conclusions. ME/PS-modified ICAM- I 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.