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Cited by 1,216RNA Interference and Gene DeliveryDNA and Nucleic Acid ChemistryRNA and protein synthesis mechanisms

The chemical evolution of oligonucleotide therapies of clinical utility

Open access
Khvorova, Anastasia, Watts, Jonathan K·2017·Nature Biotechnology
DOI 10.1038/nbt.3765PMC PMC5517098
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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.

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  • PS modifications are essential for clinically-advanced siRNA configurations.

    “PS modifications are also essential for clinically-advanced siRNA configurations1, 16.”

    From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [1]

    In “Chemical evolution of siRNAs > Metabolic stabilization” (page unavailable), the paper says phosphorothioate modifications are incorporated into many leading clinical siRNA candidates and improve nuclease resistance and in-vivo accumulation. It does not say they are essential to clinically advanced siRNA configurations; “many” does not establish necessity. (LLM, conf=0.88)

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Authors
Khvorova, A., & Watts, J. K.
Affiliations
University of Massachusetts Chan Medical School (US)
ORCID
Venue
Nature Biotechnology
Publisher
Springer Science and Business Media LLC
Published
2017-02-27
Volume
35
Issue
3
Pages
238-248
ISSN
  • 0733-222X (ISSN-L)
  • 1087-0156
  • 1546-1696
DOI
10.1038/nbt.3765
PMC
PMC5517098
OpenAlex
W2592524531
Cited by
1,216
References
8
Citations by year
2026: 146 · 2025: 127 · 2024: 149 · 2023: 141 · 2022: 140 · 2021: 150 · 2020: 115 · 2019: 117 · 2018: 89 · 2017: 42
FWCI
9.29
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Biotechnology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
Funders
  • National Institutes of Health (UH3TR000888)
  • National Institute of General Medical Sciences (R01GM108803)
  • National Center for Advancing Translational Sciences
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD086111)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
oligonucleotide therapeutics, chemical modification, gene silencing, antisense oligonucleotides, oligonucleotide delivery, sugar modification, backbone modification, nucleobase modification, liver targeting, drug safety, clinical efficacy, tissue-specific drug delivery
MeSH terms
RNAi Therapeutics, Animals, Humans, RNA, Drug Design, Oligonucleotides, Antisense, Molecular Targeted Therapy

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