ABSTRACT
INTRODUCTION The specifi c binding of synthetic oligonucleotides to cellular RNA through Watson-Crick base pairing can result in modulation of gene expression. This is the basis of the antisense concept, the therapeutic potential of which was fi rst enunciated over 30 years ago by Zamecnik ( 1 ). The majority of oligonucleotides studied to date elicit their pharmacological effects by altering the metabolism of coding RNA (mRNA), that is, RNA that is ultimately translated into protein. Various steps in the processing of mRNA are amenable to intervention with antisense oligonucleotides, and oligonucleotides designed to alter splicing ( 2 ), to inhibit 5′-capping ( 3 ), and to prevent 3′-polyadenylation ( 4 ) have all demonstrated activity in vivo, but the most studied group of antisense oligonucleotides is that designed to promote RNase H-mediated cleavage of mRNA. In addition to mRNA targets, the recent realization that noncoding RNA plays a more important role regulating protein expression than was previously suspected has opened up new classes of RNA as potential therapeutic targets ( 5 ). Finally, while the majority of therapeutic oligonucleotides seek to manipulate gene expression (by targeting RNA), oligonucleotides designed to modulate the immune response ( 6 ) and oligonucleotides that bind to protein targets by virtue of possessing discrete three-dimensional structures [called aptamers ( 7 )] are also the subjects of intense clinical research and development.
