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.
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We thank M. Osborn for the oligonucleotide image in Figure 1. We would like to acknowledge the oligonucleotide research community who contributed to the evolution of this field, including those whose excellent work we could not mention for lack of space. We thank D. Conte for significant help with manuscript preparation. This work was supported by the RNA Therapeutics Institute of University of Massachusetts Medical School, the CHDI Foundation, and US National Institutes of Health grants R01GM1088030181, R01HD086111, and UH3TR000888 to A.K.
A.K. owns stock in RXi Pharmaceuticals.
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Khvorova, A., Watts, J. The chemical evolution of oligonucleotide therapies of clinical utility. Nat Biotechnol 35, 238–248 (2017). https://doi.org/10.1038/nbt.3765
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