Oligonucleotide therapeutics: Past, present and future

Abstract

Over the past decade, oligonucleotide-based therapeutics such as antisense oligonucleotides, small interfering RNAs (siRNAs), decoy and aptamer have been developed extensively. For example, mipomersen (Kynamro; Isis Pharmaceuticals), which is a second-generation antisense oligonucleotide administered by subcutaneous injection, has recently been approved by the FDA for the treatment of homozygous familial hypercholesterolemia. In addition, microRNA (miRNA)-related oligonucleotide therapeutics, such as miRNA-targeting antisense oligonucleotides and miRNA mimics, and CpG-motif oligodeoxynucleotides (CpG ODN) have also been developed recently. The increase in research of oligonucleotide therapeutics was largely a result of improvements in the methods used for DNA sequencing, synthesizing oligonucleotides and chemically-modified nucleic acids. The most notable discovery was the addition of a phosphorothioate backbone to the oligonucleotides (S-oligo), leading to a significant increase in their stability. Other important milestone was development of a series of sugar-modified nucleic acids, including 2′-O-methyl, 2′-O-methoxyethyl, 2′-flouro and bridged nucleic acids, that remarkably increase the efficacy, stability and patentability of the oligonucleotide therapeutics. In this review, I would like to overview fundamental characteristics of oligonucleotide therapeutics, such as classification, sizes, lengths, modifications, forms, mechanism of action, kinetics and drug delivery system, and introduce global developmental trends of antisense oligonucleotides, siRNAs, miRNA-related oligonucleotide therapeutics, decoy, aptamer and CpG ODN.