Serial incorporation of a monovalent GalNAc phosphoramidite unit into hepatocyte-targeting antisense oligonucleotides

Yamamoto, Tsuyoshi; Sawamura, Motoki; Wada, Fumito; Harada‐Shiba, Mariko; Obika, Satoshi

doi:10.1016/j.bmc.2015.11.036

Cited by 40 publications

(38 citation statements)

References 23 publications

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“…However, since in contrast to siRNAs, the unmodified ASOs also accumulate efficiently in liver, the fold enhancement observed for GalNac conjugated ASOs was not as great as that described for siRNAs. This exciting technology has elicited the interest of many groups and various publications on the chemistry and biology of GalNac oligonucleotide conjugates are starting to appear (262–264). …”

Section: Approaches To Deliverymentioning

confidence: 99%

The delivery of therapeutic oligonucleotides

2016

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The oligonucleotide therapeutics field has seen remarkable progress over the last few years with the approval of the first antisense drug and with promising developments in late stage clinical trials using siRNA or splice switching oligonucleotides. However, effective delivery of oligonucleotides to their intracellular sites of action remains a major issue. This review will describe the biological basis of oligonucleotide delivery including the nature of various tissue barriers and the mechanisms of cellular uptake and intracellular trafficking of oligonucleotides. It will then examine a variety of current approaches for enhancing the delivery of oligonucleotides. This includes molecular scale targeted ligand-oligonucleotide conjugates, lipid- and polymer-based nanoparticles, antibody conjugates and small molecules that improve oligonucleotide delivery. The merits and liabilities of these approaches will be discussed in the context of the underlying basic biology.

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Section: Approaches To Deliverymentioning

confidence: 99%

The delivery of therapeutic oligonucleotides

2016

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“…Yamamoto et al 108 . observed that LNA-modified ASOs tethered to a synthetically accessible, phosphodiester-linked monovalent GalNAc unit at the 5′ terminus showed ideal potency in vivo.…”

Section: Introductionmentioning

confidence: 99%

Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

Huang

2017

Molecular Therapy - Nucleic Acids

236

203

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A main challenge in realizing the full potential of nucleic acid therapeutics is efficient delivery of them into targeted tissues and cells. N-acetylgalactosamine (GalNAc) is a well-defined liver-targeted moiety benefiting from its high affinity with asialoglycoprotein receptor (ASGPR). By conjugating it directly to the oligonucleotides or decorating it to a certain delivery system as a targeting moiety, GalNAc has achieved compelling successes in the development of nucleic acid therapeutics in recent years. Several oligonucleotide modalities are undergoing pivotal clinical studies, followed by a blooming pipeline in the preclinical stage. This review covers the progress of GalNAc-decorated oligonucleotide drugs, including siRNAs, anti-miRs, and ASOs, which provides a panorama for this field.

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“…The structure-activity relationship between the optimal number of GalNAc residues and the linkage to the cargo have been extensively evaluated [62]. Recent advances involved GalNAc to deliver siRNAs, anti-microRNAs and antisense oligonucleotides for gene silencing in hepatocytes [62][63][64][65][66]. Initial clinical phase I trials found conjugates of a tri-GalNAc construct with antisense oligonucleotides to be highly potent and with a high margin of safety [67,68].…”

Section: Asgr1mentioning

confidence: 99%

ASGR1 and Its Enigmatic Relative, CLEC10A

Hoober

2020

IJMS

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The large family of C-type lectin (CLEC) receptors comprises carbohydrate-binding proteins that require Ca2+ to bind a ligand. The prototypic receptor is the asialoglycoprotein receptor-1 (ASGR1, CLEC4H1) that is expressed primarily by hepatocytes. The early work on ASGR1, which is highly specific for N-acetylgalactosamine (GalNAc), established the foundation for understanding the overall function of CLEC receptors. Cells of the immune system generally express more than one CLEC receptor that serve diverse functions such as pathogen-recognition, initiation of cellular signaling, cellular adhesion, glycoprotein turnover, inflammation and immune responses. The receptor CLEC10A (C-type lectin domain family 10 member A, CD301; also called the macrophage galactose-type lectin, MGL) contains a carbohydrate-recognition domain (CRD) that is homologous to the CRD of ASGR1, and thus, is also specific for GalNAc. CLEC10A is most highly expressed on immature DCs, monocyte-derived DCs, and alternatively activated macrophages (subtype M2a) as well as oocytes and progenitor cells at several stages of embryonic development. This receptor is involved in initiation of TH1, TH2, and TH17 immune responses and induction of tolerance in naïve T cells. Ligand-mediated endocytosis of CLEC receptors initiates a Ca2+ signal that interestingly has different outcomes depending on ligand properties, concentration, and frequency of administration. This review summarizes studies that have been carried out on these receptors.

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Serial incorporation of a monovalent GalNAc phosphoramidite unit into hepatocyte-targeting antisense oligonucleotides

Cited by 40 publications

References 23 publications

The delivery of therapeutic oligonucleotides

The delivery of therapeutic oligonucleotides

Preclinical and Clinical Advances of GalNAc-Decorated Nucleic Acid Therapeutics

ASGR1 and Its Enigmatic Relative, CLEC10A

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