Targeting RNA with synthetic oligonucleotides: Clinical success invites new challenges

Abstract

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.

Figure 1.. Oligonucleotide drugs designed to recognize target RNAs

(A) Approved oligonucleotide therapeutics by type and mechanism of action. (B) Approval of oligonucleotide therapeutics over the past decade.

Figure 2.. Nucleic acid therapeutic mechanisms of action

(A) Recruitment of RNase H by gapmer ASOs. (B) Modulating splicing by ASOs. (C) Messenger RNA (mRNA) transcript cleavage by dsRNA therapeutics through an RNAi-mediated mechanism.

Figure 3.. Chemical modifications of oligonucleotide therapeutics.

Primary chemical modifications used in the discovery and development of oligonucleotide drugs.

Figure 4.. Targeting nucleic acid therapeutics

(A) Targeting hepatocytes via the GalNAc tag to the liver. (B) Antibody-oligonucleotide conjugates.

Figure 5.. Development of n=1 therapies.

Schematic showing the workflow for rapidly developing strategies to use synthetic nucleic acids to treat diseases with from one to a handful of patients.

Figure 6.. Leqvio, an oligonucleotide therapeutic with the potential to treat a large patient population.

Schematic showing the balance between the benefits promised by Leqvio and the challenges confronting widespread clinical adoption.