Chemistry, structure and function of approved oligonucleotide therapeutics

Abstract Eighteen nucleic acid therapeutics have been approved for treatment of various diseases in the last 25 years. Their modes of action include antisense oligonucleotides (ASOs), splice-switching oligonucleotides (SSOs), RNA interference (RNAi) and an RNA aptamer against a protein. Among the di...

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Bibliographic Details
Published in:Nucleic acids research Vol. 51; no. 6; pp. 2529 - 2573
Main Authors: Egli, Martin, Manoharan, Muthiah
Format: Journal Article
Language:English
Published: England Oxford University Press 11.04.2023
Subjects:
Critical Reviews and s
Humans
Morpholinos - pharmacology
Muscular Dystrophy, Duchenne - drug therapy
Muscular Dystrophy, Duchenne - genetics
Oligonucleotides, Antisense - chemistry
Oligonucleotides, Antisense - metabolism
Oligonucleotides, Antisense - therapeutic use
RNA - chemistry
RNA Interference
ISSN:0305-1048, 1362-4962, 1362-4962
Online Access:Get full text
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Summary:Abstract Eighteen nucleic acid therapeutics have been approved for treatment of various diseases in the last 25 years. Their modes of action include antisense oligonucleotides (ASOs), splice-switching oligonucleotides (SSOs), RNA interference (RNAi) and an RNA aptamer against a protein. Among the diseases targeted by this new class of drugs are homozygous familial hypercholesterolemia, spinal muscular atrophy, Duchenne muscular dystrophy, hereditary transthyretin-mediated amyloidosis, familial chylomicronemia syndrome, acute hepatic porphyria, and primary hyperoxaluria. Chemical modification of DNA and RNA was central to making drugs out of oligonucleotides. Oligonucleotide therapeutics brought to market thus far contain just a handful of first- and second-generation modifications, among them 2′-fluoro-RNA, 2′-O-methyl RNA and the phosphorothioates that were introduced over 50 years ago. Two other privileged chemistries are 2′-O-(2-methoxyethyl)-RNA (MOE) and the phosphorodiamidate morpholinos (PMO). Given their importance in imparting oligonucleotides with high target affinity, metabolic stability and favorable pharmacokinetic and -dynamic properties, this article provides a review of these chemistries and their use in nucleic acid therapeutics. Breakthroughs in lipid formulation and GalNAc conjugation of modified oligonucleotides have paved the way to efficient delivery and robust, long-lasting silencing of genes. This review provides an account of the state-of-the-art of targeted oligo delivery to hepatocytes.
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ISSN:0305-1048
1362-4962
1362-4962
DOI:10.1093/nar/gkad067