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Antisense oligodeoxynucleotide and ribozyme design.

The overwhelming advances of the last few years in the field of nucleic acid-based technologies laid the basis for the development of this new technology as a frontier method not only to combat diseases and infections but also to study gene function. The development of antisense strategies has generated considerable expectations in the neurosciences and, in particular, behavioral neurobiology. Antisense application in the brain has become a technology with tremendous impact, especially for determining the molecular pathways and substrates of behavior of an organism controlled by independent stimuli. The antisense agents, either oligodeoxynucleotides or ribozymes, interfere in the genetic flow of information from DNA via RNA to protein. According to the literature it seems clear that appropriately modified antisense compounds successfully and stably bind to their target ribonucleic acid molecules. This antisense binding leads to a decrease in the corresponding protein levels. If the targeted protein exerts detrimental effects on the cell or tissue, its reduction should be beneficial from a therapeutic point of view. If the investigator wants to study the function of a specific gene product the selective and transient downregulation of the corresponding target protein will help in functional analysis. In the following article I describe the chemical nature of the antisense oligodeoxynucleotides and some of the most commonly used derivatives and give some guidelines on antisense construction and application. The possible mode of action is discussed, as is expansion of the oligonucleotide-based application to ribozyme-mediated gene inhibition. Finally, problems that may be encountered during antisense application are discussed.