Development of antisense oligodeoxynucleotides for transplantation.

Abstract

Over last ten years antisense technology has been improved to provide powerful tools to selectively inhibit production of different mRNAs. This technology has been applied in transplantation to prolong the survival of organ allografts and to prevent development of ischemic/reperfusion injury in grafts. The present review describes technological progress in chemical modifications from antisense phosphodiester oligonucleotides to phosphorothioate oligonucleotides and the most advanced chimeric oligonucleotides with methoxyethyl groups attached at both ends or at one end of the oligonucleotide. Results indicate that phosphorothioate oligonucleotides, designed to block intercellular adhesion molecule-1 (ICAM-1), extended the survival of heart and kidney allografts when administered to donors or recipients. Combination of ICAM-1 antisense phosphorothioate oligonucleotide and cyclosporine (CsA) produced a potent synergistic interaction on allograft survival in comparison with each drug alone. The same ICAM-1 phosphorothioate oligonucleotide used for perfusion of kidney grafts prevented development of ischemic/reperfusion injury. We also compared the effect of c-raf mRNA inhibition on heart allograft survival by phosphorothioate oligonucleotide or phosphorothioate/methoxyethyl oligonucleotide used alone or in combination with CsA or sirolimus (SRL). The results documented that addition of methoxyethyl modifications at both ends or at one end of oligonucleotides significantly improved the in vivo antisense activity. Combined therapy with c-raf antisense phosphorothioate/methoxyethyl oligonucleotide and SRL synergistically extended the survival of heart allografts. Thus, antisense technology may provide not only tools to examine the effects of selective inhibition of different molecules involved in allograft rejection but also act as potential therapeutic agents.