ArticleNature biotechnology2021
Cholesterol-functionalized DNA/RNA heteroduplexes cross the blood-brain barrier and knock down genes in the rodent CNS.
Article in Nature biotechnology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.
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Who cites it
73 citing papers in PubMed, 136 citations in OpenAlex.
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- Fatty-acid-based antimiR-23b delivery in the DMSXL model: A potential therapeutic strategy for brain dysfunction in myotonic dystrophy type 1.Cell reports. Medicine · 2026Article
- Single-dose administration of therapeutic divalent siRNA targeting MECP2 prevents lethality in an MECP2 duplication mouse model.Nature communications · 2026Article
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- Staple oligomers induce a stable RNA G-quadruplex structure for protein translation inhibition in therapeutics.Nature biomedical engineering · 2026Article
- A historical perspective on the development of antisense oligonucleotide treatments for Duchenne muscular dystrophy and spinal muscular atrophy.Journal of neuromuscular diseases · 2026Review
- Bioconjugates for improved delivery of oligonucleotide therapeutics to the central nervous system.Advanced drug delivery reviews · 2026Review
- Heteroduplex oligonucleotide technology boosts gene knockdown in cardiac and skeletal muscles.Nucleic acids research · 2026Article
- DNA/RNA Heteroduplex Oligonucleotide for Highly Efficient Gene Silencing.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.Molecular neurodegeneration advances · 2026Review
- APOE Lipoprotein Particles: Pathophysiology, Therapy, and the Crosstalk in Alzheimer's Disease and Cardiovascular Disease.Molecular neurobiology · 2025Review
- Morpholino-RNA duplex exhibits robust, sustained, and safe steric-block antisense activity by intracerebroventricular and intrathecal injection.Nature communications · 2025Article
- Chemical strategies for brain delivery of genomic therapy.Nature reviews. Chemistry · 2025Review
- Intravenous lipid-siRNA conjugate mediates gene silencing at the blood-brain barrier and blood-CSF barrier.Journal of controlled release : official journal of the Controlled Release Society · 2025Article
- RNA chemistry and therapeutics.Nature reviews. Drug discovery · 2025Review
- Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system.Nature biotechnology · 2025Article
- Cleavable Hydrophobic Anchors Optimize Immunomodulatory Effects of Oligonucleotides.Journal of the American Chemical Society · 2025Article
- Angelman syndrome patient-derived neuron screen leads to clinical ASO rugonersen targeting UBE3A-ATS with long-lasting effect in monkeys.Nucleic acids research · 2025Article
- Effect of cholesterol on distribution, cell uptake, and protein corona of lipid microspheres at sites of cardiovascular inflammatory injury.Journal of pharmaceutical analysis · 2025Article
13 more citing papers are in PubMed but not listed here.
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Authors and funding
24 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Achieving regulation of endogenous gene expression in the central nervous system (CNS) with antisense oligonucleotides (ASOs) administered systemically would facilitate the development of ASO-based therapies for neurological diseases. We demonstrate that DNA/RNA heteroduplex oligonucleotides (HDOs) conjugated to cholesterol or α-tocopherol at the 5' end of the RNA strand reach the CNS after subcutaneous or intravenous administration in mice and rats. The HDOs distribute throughout the brain, spinal cord and peripheral tissues and suppress the expression of four target genes by up to 90% in the CNS, whereas single-stranded ASOs conjugated to cholesterol have limited activity. Gene knockdown was observed in major CNS cell types and was greatest in neurons and microglial cells. Side effects, such as thrombocytopenia and focal brain necrosis, were limited by using subcutaneous delivery or by dividing intravenous injections. By crossing the blood-brain barrier more effectively, cholesterol-conjugated HDOs may overcome the limited efficacy of ASOs targeting the CNS without requiring intrathecal administration.
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