ArticleMolecular therapy. Nucleic acids2020
Less Is More: Novel Hepatocyte-Targeted siRNA Conjugates for Treatment of Liver-Related Disorders.
Article in Molecular therapy. Nucleic acids, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Refined Design and Liquid-Phase Assembly of GalNAc-siRNA Conjugates: Comparative Efficiency Validation in PCSK9 Targeting.Molecules (Basel, Switzerland) · 2026Article
- RNA-Targeted Therapeutics for Lipid Metabolic Disorders: From Bench to Bedside.Research (Washington, D.C.) · 2026Article
- Emerging Approaches for the Treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease: The Application of Nanomedicines.International journal of nanomedicine · 2026Review
- Metabolic Dysfunction-Associated Steatotic Liver Disease and Emerging Oligonucleotide Therapies.International journal of biological sciences · 2026Review
- Inverted chimeric RNAi molecules synergistically cotarget MYC and KRAS in KRAS-driven cancers.The Journal of clinical investigation · 2025Article
- Development of bioconjugate-based delivery systems for nucleic acids.RNA (New York, N.Y.) · 2024Review
- The beauty of symmetry: siRNA phosphorodithioate modifications reduce stereocomplexity, ease analysis, and can improveMolecular therapy. Nucleic acids · 2024Article
- Application of improved GalNAc conjugation in development of cost-effective siRNA therapies targeting cardiovascular diseases.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Glycomimetics for the inhibition and modulation of lectins.Chemical Society reviews · 2023Review
- Targeted delivery of oligonucleotides using multivalent protein-carbohydrate interactions.Chemical Society reviews · 2023Review
- Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage.Nature communications · 2022Article
- Silencing of ceramide synthase 2 in hepatocytes modulates plasma ceramide biomarkers predictive of cardiovascular death.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- Treatment and prevention of lipoprotein(a)-mediated cardiovascular disease: the emerging potential of RNA interference therapeutics.Cardiovascular research · 2022Review
- Engineering miRNA features into siRNAs: Guide-strand bulges are compatible with gene repression.Molecular therapy. Nucleic acids · 2022Article
- Nanotechnology-Assisted RNA Delivery: From Nucleic Acid Therapeutics to COVID-19 Vaccines.Small methods · 2021Review
- Feasibility of cRGD conjugation at 5'-antisense strand of siRNA by phosphodiester linkage extension.Molecular therapy. Nucleic acids · 2021Article
- Rare Treatments for Rare Dyslipidemias: New Perspectives in the Treatment of Homozygous Familial Hypercholesterolemia (HoFH) and Familial Chylomicronemia Syndrome (FCS).Current atherosclerosis reports · 2021Review
- SLN124, a GalNac-siRNA targeting transmembrane serine protease 6, in combination with deferiprone therapy reduces ineffective erythropoiesis and hepatic iron-overload in a mouse model of β-thalassaemia.British journal of haematology · 2021Article
- Understanding In Vivo Fate of Nucleic Acid and Gene Medicines for the Rational Design of Drugs.Pharmaceutics · 2021Review
- Epigenetic mechanisms in hepatitis B virus-associated hepatocellular carcinoma.Hepatoma research · 2021Article
Corrections and comments
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
N-acetyl-galactosamine (GalNAc) conjugation enhances liver specificity for therapeutic oligonucleotides. Here we report on a novel design with improved activity and stability compared with a triantennary design. We applied a versatile monovalent serinol-GalNAc conjugation strategy. First, 1-4 serial serinol-linked GalNAc units were conjugated to terminal positions of small interfering RNA (siRNA) molecules. In primary hepatocytes, 5' antisense GalNAc conjugates were inactive, whereas 3' antisense and 3' or 5' sense conjugates displayed low activity for single GalNAc units, while 2-4 serial GalNAc conjugates were all equally potent. In mice, 5' sense conjugates with 2-4 serial GalNAc units were all as potent as a triantennary GalNAc control (1 mg/kg). Second, increased spacing between two serial 5' sense-conjugated GalNAc units did not affect in vitro activity. Finally, two single GalNAc units were positioned at opposite ends of the sense strand. A single dose (0.3 mg/kg) of this novel conjugate in mice showed a 3-fold reduction of serum target protein level at day 7 and 4-fold lower serum level at day 27, relative to an equimolar dose of a triantennary GalNAc conjugate of the same siRNA. Improved tritosome stability (by liquid chromatography-mass spectrometry [LC-MS] analysis) can at least partially explain the increased activity and duration of action for the novel GalNAc conjugate.
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