ArticleNucleic acids research2020
Understanding the effect of controlling phosphorothioate chirality in the DNA gap on the potency and safety of gapmer antisense oligonucleotides.
Article in Nucleic acids research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 96 citations in OpenAlex.
- Chemical Modification Strategies for Therapeutic Oligonucleotides: Mechanism Compatibility, Design Trade-Offs, and Translational Barriers.Molecules (Basel, Switzerland) · 2026Review
- The Versatile Applications of Antisense Oligonucleotides in Modern Medicine.International journal of molecular sciences · 2026Review
- Synthesis of highly complex phosphorothioate-modified oligonucleotides on microarrays.Scientific reports · 2026Article
- Advances in Analysis of Therapeutic Oligonucleotides with Chromatography Coupled to Mass Spectrometry.Analytical chemistry · 2026Review
- Chemical cleavage coupled with LCMS to report on the true diastereomeric distributions of phosphorothioate linkages in gapmer ASO.Analytical and bioanalytical chemistry · 2026Article
- Genetic therapies for neurological diseases.Pharmacological reviews · 2026Review
- Stereo-random oligonucleotides enable efficient recruitment of ADAR in vitro and in vivo.Nature communications · 2025Article
- Discovery and characterization of stereodefined PMO-gapmers targeting tau.Molecular therapy. Nucleic acids · 2025Article
- Landscape of small nucleic acid therapeutics: moving from the bench to the clinic as next-generation medicines.Signal transduction and targeted therapy · 2025Review
- Chemical Modifications in Nucleic Acid Therapeutics.Methods in molecular biology (Clifton, N.J.) · 2025Review
- Small nucleic acid drugs-the dawn of functional cure of chronic hepatitis B.Frontiers in pharmacology · 2025Review
- Technologies for Targeted RNA Degradation and Induced RNA Decay.Chemical reviews · 2024Review
- The bench to bedside journey of tricyclo-DNA antisense oligonucleotides for the treatment of Duchenne muscular dystrophy.RSC medicinal chemistry · 2024Review
- Splice-switching antisense oligonucleotide controlling tumor suppressor REST is a novel therapeutic medicine for neuroendocrine cancer.Molecular therapy. Nucleic acids · 2024Article
- Structural dynamics of therapeutic nucleic acids with phosphorothioate backbone modifications.NAR genomics and bioinformatics · 2024Article
- Targeting RNA with synthetic oligonucleotides: Clinical success invites new challenges.Cell chemical biology · 2024Review
- Dynamic and static control of the off-target interactions of antisense oligonucleotides using toehold chemistry.Nature communications · 2023Article
- An enhanced biophysical screening strategy to investigate the affinity of ASOs for their target RNA.RSC chemical biology · 2023Article
- The promise of RNA-based therapeutics in revolutionizing heart failure management - a narrative review of current evidence.Annals of medicine and surgery (2012) · 2023Review
- Differential effects of SARM1 inhibition in traumatic glaucoma and EAE optic neuropathies.Molecular therapy. Nucleic acids · 2023Article
Corrections and comments
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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
Therapeutic oligonucleotides are often modified using the phosphorothioate (PS) backbone modification which enhances stability from nuclease mediated degradation. However, substituting oxygen in the phosphodiester backbone with sulfur introduce chirality into the backbone such that a full PS 16-mer oligonucleotide is comprised of 215 distinct stereoisomers. As a result, the role of PS chirality on the performance of antisense oligonucleotides (ASOs) has been a subject of debate for over two decades. We carried out a systematic analysis to determine if controlling PS chirality in the DNA gap region can enhance the potency and safety of gapmer ASOs modified with high-affinity constrained Ethyl (cEt) nucleotides in the flanks. As part of this effort, we examined the effect of systematically controlling PS chirality on RNase H1 cleavage patterns, protein mislocalization phenotypes, activity and toxicity in cells and in mice. We found that while controlling PS chirality can dramatically modulate interactions with RNase H1 as evidenced by changes in RNA cleavage patterns, these were insufficient to improve the overall therapeutic profile. We also found that controlling PS chirality of only two PS linkages in the DNA gap was sufficient to modulate RNase H1 cleavage patterns and combining these designs with simple modifications such as 2'-OMe to the DNA gap resulted in dramatic improvements in therapeutic index. However, we were unable to demonstrate improved potency relative to the stereorandom parent ASO or improved safety over the 2'-OMe gap-modified stereorandom parent ASO. Overall, our work shows that while controlling PS chirality can modulate RNase H1 cleavage patterns, ASO sequence and design are the primary drivers which determine the pharmacological and toxicological properties of gapmer ASOs.
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