Antisense oligonucleotides: a new therapeutic approach.

The use of antisense oligonucleotides as therapeutic agents has heralded a new field of genetic pharmacology. Oligonucleotides are relatively easy to design and display increased affinity and selectivity for their nucleic acid targets compared with traditional drugs. However, the development of antisense therapy has not been as simple as was first believed; many critical issues had to be addressed. The first generation of oligonucleotides investigated as drug candidates were phosphorothioate oligonucleotides. Several animal experiments have provided evidence that antisense oligonucleotides can inhibit gene expression of disease-associated proteins. These promising studies led to the advancement of these compounds into clinical trials in such diverse fields as infectious diseases, cancer and inflammation. The insights gained through ongoing clinical trials has opened the pathway to the design of second-generation oligonucleotides which have an improved safety profile and efficacy.