The chemical evolution of oligonucleotide therapies of clinical utility

Abstract

After nearly 40 years of development, oligonucleotide therapeutics are nearing meaningful clinical productivity. One of the key advantages of oligonucleotide drugs is that their delivery and potency are derived primarily from the chemical structure of the oligonucleotide whereas their target is defined by the base sequence. Thus, as oligonucleotides with a particular chemical design show appropriate distribution and safety profiles for clinical gene silencing in a particular tissue, this will open the door to the rapid development of additional drugs targeting other disease-associated genes in the same tissue. To achieve clinical productivity, the chemical architecture of the oligonucleotide needs to be optimized with a combination of sugar, backbone, nucleobase, and 3'- and 5'-terminal modifications. A portfolio of chemistries can be used to confer drug-like properties onto the oligonucleotide as a whole, with minor chemical changes often translating into major improvements in clinical efficacy. One outstanding challenge in oligonucleotide chemical development is the optimization of chemical architectures to ensure long-term safety. There are multiple designs that enable effective targeting of the liver, but a second challenge is to develop architectures that enable robust clinical efficacy in additional tissues.

Figure 1. The key advantage of an informational drug

is that the pharmacophore (molecular features that determine target specificity) and the dianophore (molecular features that determine tissue distribution and metabolism) can be optimized separately. When a dianophore for a particular tissue or cell type is defined, it can be applied to a range of pharmacophores that are rationally designed based on sequence information.

Figure 2. Structures of chemical modifications discussed in this review

Combining modifications of the oligonucleotide backbone, sugars, bases and the 5′-phosphate are necessary to develop compounds with optimal activity. Some modifications are used for oligonucleotides that work by different mechanisms: steric blockers, green; RNase H, blue; RNAi, orange lines.

Figure 3. The evolution of RNase H antisense and RNAi technologies, including key chemical modifications and structural configurations that have enabled major advances toward clinical efficacy

○ White circles, 2′-OH (RNA), or 2′-H (DNA); Gray, 2′-F; ● Black, 2′-OMe or 2′-MOE; Blue, LNA or cEt, Green, specificity enhancing modification; red, phosphorothioate backbone modification (direction of the bond indicates positional stereopurity R_p or S_p). PUFA, polyunsaturated fatty acids; gen 2, second generation.

Figure 4. Key events in antisense and RNAi therapeutics mapped to the Technology Curve

Both antisense (a) and RNAi (b) approaches have passed through the stages of novel technology trigger, peak of inflated expectations, and trough of disillusionment and are now approaching the plateau of productivity.