NOT NONSENSE BUT ANTISENSE - APPLICATIONS OF ANTISENSE OLIGONUCLEOTIDES IN DIFFERENT FIELDS OF MEDICINE

This brief overview will give the reader an idea what antisense oligon ucleotides are, how they act, what one can do with them, and what futu re perspectives might emerge. The idea behind this new therapeutic str ategy is the selective blockage of a specific gene in vivo, which is r esponsible for a certain disease. Antisense oligonucleotides are short , traditionally 15 to 25 bases long, single stranded DNA fragments, wh ich are targeted against a specific mRNA. This is the classical antise nse mechanism. These DNA fragments can also be targeted against a spec ific genomic DNA sequence which is known as antigene therapy. The olig onucleotides have to be modified in order to increase their stability in vivo. Three mechanisms of action have been reported for the oligonu cleotides: 1. Oligonucleotides are designed in a complementary (antise nse) orientation to their target (sense) mRNA to which they hybridize in a strictly base pair specific manner (Watson-Crick base pairing) an d thus block translation. 2. They can bind to the genomic DNA in the n ucleus and thus block transcription (Hoogsten-type base triplets). A t hird, unspecific mechanism of action is the binding of the oligonucleo tide to a target protein in what has been referred to as aptamer-bindi ng. In addition, other nonspecific effects of cytokine and neutrophil activation were observed. The antisense strategy is a useful research tool for the identification of specific gene-protein functions. The fi rst in vivo animal studies and clinical experiences have been carried out in the fields of cardiovascular medicine. oncology and virology yi elding promising results. Currently, the first clinical trials using a ntisense oligonucleotides for the inhibition of gene expression are be ing performed. the results will be available in the next years.