ArticleNucleic acids research2022
Impact of guanidine-containing backbone linkages on stereopure antisense oligonucleotides in the CNS.
Article in Nucleic acids research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 68 citations in OpenAlex.
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- Amidation of Phosphonoacetate-Modified Oligonucleotides and Evaluation of the Properties of the Synthesized Oligonucleotides.Organic letters · 2026Article
- Chemical cleavage coupled with LCMS to report on the true diastereomeric distributions of phosphorothioate linkages in gapmer ASO.Analytical and bioanalytical chemistry · 2026Article
- Expanding the Range of Methods for Obtaining Diverse Representatives of Sulfonyl Phosphoramidate Oligonucleotides.ACS omega · 2026Article
- RNA editing for the treatment of alpha-1 antitrypsin deficiency.Nucleic acids research · 2026Article
- Antisense oligonucleotides to KIF1A polymorphisms expand targets and rescue patient-derived neurons in vitro.Nature communications · 2026Article
- Genetic therapies for neurological diseases.Pharmacological reviews · 2026Review
- Progress and prospects in antisense oligonucleotide-mediated exon skipping therapies for Duchenne muscular dystrophy.Journal of muscle research and cell motility · 2025Review
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- Single alkyl phosphonate modification of the siRNA backbone in the seed region enhances specificity and therapeutic profile.Nucleic acids research · 2025Article
- Solution-Phase Synthesis of Boranophosphate and Boranophosphate/Phosphorothioate/Phosphate Chimeric Oligonucleotides via the H-Boranophosphonate Method.The Journal of organic chemistry · 2025Article
- Discovery and characterization of stereodefined PMO-gapmers targeting tau.Molecular therapy. Nucleic acids · 2025Article
- Application of antisense oligonucleotide drugs in amyotrophic lateral sclerosis and Huntington's disease.Translational neurodegeneration · 2025Review
- A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD.Nature communications · 2025Article
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Authors and funding
37 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Attaining sufficient tissue exposure at the site of action to achieve the desired pharmacodynamic effect on a target is an important determinant for any drug discovery program, and this can be particularly challenging for oligonucleotides in deep tissues of the CNS. Herein, we report the synthesis and impact of stereopure phosphoryl guanidine-containing backbone linkages (PN linkages) to oligonucleotides acting through an RNase H-mediated mechanism, using Malat1 and C9orf72 as benchmarks. We found that the incorporation of various types of PN linkages to a stereopure oligonucleotide backbone can increase potency of silencing in cultured neurons under free-uptake conditions 10-fold compared with similarly modified stereopure phosphorothioate (PS) and phosphodiester (PO)-based molecules. One of these backbone types, called PN-1, also yielded profound silencing benefits throughout the mouse brain and spinal cord at low doses, improving both the potency and durability of response, especially in difficult to reach brain tissues. Given these benefits in preclinical models, the incorporation of PN linkages into stereopure oligonucleotides with chimeric backbone modifications has the potential to render regions of the brain beyond the spinal cord more accessible to oligonucleotides and, consequently, may also expand the scope of neurological indications amenable to oligonucleotide therapeutics.
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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 Socratic graph.