Targeting RNA with synthetic oligonucleotides: Clinical success invites new challenges

Summary

Synthetic antisense oligonucleotides (ASOs) and duplex RNAs (dsRNAs) are an increasingly successful strategy for drug development. After a slow start, the pace of success has accelerated since the approval of Spinraza (nusinersen) in 2016 with several drug approvals. These accomplishments have been achieved even though oligonucleotides are large, negatively charged, and have little resemblance to traditional small-molecule drugs—a remarkable achievement of basic and applied science. The goal of this review is to summarize the foundation underlying recent progress and describe ongoing research programs that may increase the scope and impact of oligonucleotide therapeutics.