Mechanisms of Oligonucleotide Actions

Abstract

The promise of antisense oligonucleotide (ASO) therapeutics is the ability to design drugs that are specific inhibitors of the expression solely on the basis of Watson and Crick base‐pairing rules. The premise is that treatment of a patient with a DNA‐like oligonucleotide complementary to a disease‐related RNA (usually a messenger RNA) results in the formation of a heteroduplex that inhibits the function (generally translation) of that target RNA. Although antisense RNAs were first described in 1978 [1, 2], until recently the promise of selectivity and efficacy has always remained slightly out of reach for various reasons. Oligonucleotides are large molecules leading to synthesis and delivery issues. In addition, natural DNA and RNA oligonucleotides are rapidly degraded and cleared after systemic delivery. Over time many of the issues that have challenged developers of oligonucleotide‐based therapeutics have been addressed: Synthesis costs have been reduced by orders of magnitude over the past two decades, allowing more investigators to use the technology. Stability issues were addressed partially with the introduction of phosphorothioate backbones (reviewed in Ref. [3]) and later sugar modifications (reviewed in Ref. [4]), and, as a result, oligonucleotides now used clinically and preclinically have more conventional drug‐like properties [5]. In addition, fundamental discoveries have improved our understanding of the antisense mechanisms. We now know that target RNA structure and accessibility impacts activity of oligonucleotide therapeutics [6] and therefore pharmacologic activity. Apparently small changes in Mechanisms of Oligonucleotide Actions Annemieke Aartsma‐Rus, Aimee L. Jackson, and Arthur A. Levin