Identification and characterization of second-generation antisense oligonucleotides

The use of antisense oligonuckeotides to inhibit gene expression was first proposed in 1978. Since then, considerable advances have been made in our understanding of both oligonucleotide pharmacodynamics and pharmacokinetics. This, in turn, has led to an increased appreciation of the characteristics and requirements of oligonucleotides for optimal biologic activity. Guided by this knowledge, research in oligonucleotide medicinal chemistry has sought to develop rationally chemically modified oligonucleotides capable of providing greatly improved characteristics compared with first-generation compounds. In the present short review, we attempt to describe some of the approaches taken and advances that have been made in oligonucleotide chemistry. In doing so, we highlight some of the principles and rationale that govern our research.