What question did this study set out to answer?

To determine whether conjugating triantennary N-acetyl galactosamine to antisense oligonucleotides enhances hepatocyte-specific delivery and gene-silencing potency in mouse models.

July 3, 2014Nucleic Acids ResearchOpen Access

Targeted delivery of antisense oligonucleotides to hepatocytes using triantennaryN-acetyl galactosamine improves potency 10-fold in mice

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To determine whether conjugating triantennary N-acetyl galactosamine to antisense oligonucleotides enhances hepatocyte-specific delivery and gene-silencing potency in mouse models.
Synthesized triantennary N-acetyl galactosamine (GN3) conjugates with second-generation and next-generation S-cEt gapmer antisense oligonucleotides (ASOs).
Evaluated binding affinity to mouse asialoglycoprotein receptors (ASGPR), plasma stability, and preferential delivery to hepatocytes over non-parenchymal cells.
Tested conjugated ASOs targeting human apolipoprotein C-III and transthyretin in transgenic mice to evaluate in vivo potency and duration of action.
GN3 conjugation enhanced the potency of second-generation ASOs by 6- to 10-fold and S-cEt gapmer ASOs by approximately 60-fold compared to parent MOE ASOs in mouse liver.
GN3-ASO conjugates remained intact in plasma and acted as liver-targeting prodrugs, selectively entering hepatocytes via ASGPR before metabolizing to release the active parent ASO.
Conjugation improved both the potency and duration of gene suppression for ASOs targeting human APOC3 and TTR in transgenic mice.

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Implication

Animal study demonstrates that GalNAc conjugation increases antisense oligonucleotide potency up to 60-fold in mouse liver, suggesting potential for lower doses and monthly administration.

Cite This Study

Prakash et al. (2014) studied this question.

synapsesocial.com/papers/69df6d1c4fb243fc8e59201e https://doi.org/10.1093/nar/gku531

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Implication

Animal study demonstrates that GalNAc conjugation increases antisense oligonucleotide potency up to 60-fold in mouse liver, suggesting potential for lower doses and monthly administration.

Targeted delivery of antisense oligonucleotides to hepatocytes using triantennaryN-acetyl galactosamine improves potency 10-fold in mice

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Discussion

Implication

Cite This Study

Targeted delivery of antisense oligonucleotides to hepatocytes using triantennaryN-acetyl galactosamine improves potency 10-fold in mice

Key Points

Discussion

Implication

Cite This Study

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