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Development of antisense oligodeoxynucleotides for transplantation
1Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Medical School at Houston, Houston, TX 77030, USA. sstepkow@orgtx71.med.uth.tmc.edu
Current Opinion in Molecular Therapeutics
|March 16, 2001
Summary
Antisense technology, particularly modified oligonucleotides, shows promise in prolonging organ allograft survival and preventing injury. Combined therapies demonstrate synergistic effects, highlighting potential therapeutic applications in transplantation.
Area of Science:
- Biotechnology
- Immunology
- Transplantation Medicine
Background:
- Antisense technology has advanced significantly over the past decade, offering precise methods to inhibit messenger RNA (mRNA) production.
- This technology has been explored in organ transplantation to enhance graft survival and mitigate ischemic/reperfusion injury.
Purpose of the Study:
- To review advancements in chemical modifications of antisense oligonucleotides, including phosphodiester, phosphorothioate, and chimeric structures.
- To evaluate the efficacy of antisense oligonucleotides targeting intercellular adhesion molecule-1 (ICAM-1) and c-raf mRNA in allograft survival and injury prevention.
Main Methods:
- Chemical modifications of antisense oligonucleotides were assessed, focusing on phosphorothioate and chimeric structures with methoxyethyl groups.
- Studies involved administering ICAM-1 antisense oligonucleotides to donors or recipients and evaluating heart and kidney allograft survival.
- The synergistic effects of antisense therapies combined with immunosuppressants like cyclosporine (CsA) and sirolimus (SRL) were investigated.
Main Results:
- Phosphorothioate oligonucleotides targeting ICAM-1 successfully prolonged heart and kidney allograft survival.
- Combination therapy of ICAM-1 antisense oligonucleotides with CsA showed significant synergistic benefits on allograft survival.
- ICAM-1 antisense oligonucleotides prevented ischemic/reperfusion injury in kidney grafts.
- Methoxyethyl modifications enhanced in vivo antisense activity, and combined therapy with c-raf antisense oligonucleotides and SRL synergistically extended heart allograft survival.
Conclusions:
- Antisense technology, especially with advanced chemical modifications, provides effective tools for studying and potentially treating allograft rejection.
- Modified antisense oligonucleotides, alone or in combination with existing immunosuppressants, represent promising therapeutic agents for transplantation.