Antisense oligonucleotides as therapeutic agents

Antisense oligonucleotides can block the expression of specific target gene s involved in the development of human diseases. Therapeutic applications o f antisense techniques are currently under investigation in many different fields. The use of antisense molecules to modify gene expression is variabl e in its efficacy and reliability, raising objections about their use as th erapeutic agents. However, preliminary results of several clinical studies demonstrated the safety and to some extent the efficacy of antisense oligod eoxynucleotides (ODNs) in patients with malignant diseases. Clinical respon se was observed in some patients suffering from ovarian cancer who were tre ated with antisense targeted against the gene encoding for the protein kina se C-alpha. Some hematological diseases treated with antisense oligos targe ted against the bcr/abl and the bc12 mRNAs have shown promising clinical re sponse. Antisense therapy has been useful in the treatment of cardiovascula r disorders such as restenosis after angioplasty, vascular bypass graft occ lusion, and transplant coronary vasculopathy. Antisense oligonucleotides al so have shown promise as antiviral agents. Several investigators are perfor ming trials with oligonucleotides targeted against the human immunodeficien cy virus-1 (HIV-1) and hepatitis viruses. Phosphorothioate ODNs now have re ached phase I and ii in clinical trials for the treatment of cancer and vir al infections, so far demonstrating an acceptable safety and pharmacokineti c profile for continuing their development. The new drug Vitravene, based o n a phosphorothioate oligonucleotide designed to inhibit the human cytomega lovirus (CMV), promises that some substantial successes can be reached with the antisense technique. 1999. (C) 1999 Wiley-Liss, Inc.