ArticleNucleic acids research2021
Site-specific incorporation of 5'-methyl DNA enhances the therapeutic profile of gapmer ASOs.
Article in Nucleic acids research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 45 citations in OpenAlex.
- Acyclic artificial nucleic acid substitution expands the safe design space of gapmer ASOs by preventing P54nrb mislocalization.NAR molecular medicine · 2026Article
- Navigating the next frontier in biomedicine: breakthroughs and insights in nucleic acid therapeutics.Chemical science · 2026Review
- Genetic therapies for neurological diseases.Pharmacological reviews · 2026Review
- Unraveling and controlling late-onset neurotoxicity of antisense oligonucleotides through strategic chemical modifications.Molecular therapy. Nucleic acids · 2025Article
- Article
- Hepatocyte KCTD17-mediated SERPINA3 inhibition determines liver fibrosis in metabolic dysfunction-associated steatohepatitis.Experimental & molecular medicine · 2025Article
- Efficient convergent synthesis of 1,3-diazepinone nucleosides by ring-closing metathesis and direct glycosylation.RSC advances · 2024Article
- A therapeutic approach for the hepatitis C virus: in silico design of an antisense oligonucleotide-based candidate capsid inhibitor.Virus genes · 2024Article
- KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression.Clinical and molecular hepatology · 2024Article
- Non-coding RNAs as therapeutic targets and biomarkers in ischaemic heart disease.Nature reviews. Cardiology · 2024Review
- Regulation of human microglial gene expression and function via RNAase-H active antisense oligonucleotides in vivo in Alzheimer's disease.Molecular neurodegeneration · 2024Article
- Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry.Nature communications · 2023Article
- Article
- Considerations in the Preclinical Assessment of the Safety of Antisense Oligonucleotides.Nucleic acid therapeutics · 2023Review
- Antisense oligonucleotides: a novel Frontier in pharmacological strategy.Frontiers in pharmacology · 2023Review
- Antisense Gapmers with LNA-Wings and (Molecules (Basel, Switzerland) · 2022Article
- Therapeutic Strategies in Huntington's Disease: From Genetic Defect to Gene Therapy.Biomedicines · 2022Review
- Identification of nucleobase chemical modifications that reduce the hepatotoxicity of gapmer antisense oligonucleotides.Nucleic acids research · 2022Article
- RNA modifications can affect RNase H1-mediated PS-ASO activity.Molecular therapy. Nucleic acids · 2022Article
- Preclinical Safety Assessment of Therapeutic Oligonucleotides.Methods in molecular biology (Clifton, N.J.) · 2022Article
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We recently showed that site-specific incorporation of 2'-modifications or neutral linkages in the oligo-deoxynucleotide gap region of toxic phosphorothioate (PS) gapmer ASOs can enhance therapeutic index and safety. In this manuscript, we determined if introducing substitution at the 5'-position of deoxynucleotide monomers in the gap can also enhance therapeutic index. Introducing R- or S-configured 5'-Me DNA at positions 3 and 4 in the oligodeoxynucleotide gap enhanced the therapeutic profile of the modified ASOs suggesting a different positional preference as compared to the 2'-OMe gap modification strategy. The generality of these observations was demonstrated by evaluating R-5'-Me and R-5'-Ethyl DNA modifications in multiple ASOs targeting HDAC2, FXI and Dynamin2 mRNA in the liver. The current work adds to a growing body of evidence that small structural changes can modulate the therapeutic properties of PS ASOs and ushers a new era of chemical optimization with a focus on enhancing the therapeutic profile as opposed to nuclease stability, RNA-affinity and pharmacokinetic properties. The 5'-methyl DNA modified ASOs exhibited excellent safety and antisense activity in mice highlighting the therapeutic potential of this class of nucleic acid analogs for next generation ASO designs.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.