Europe PMC

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.

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

Author information

Affiliations

  • 1. Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA.
      Authors
    • Prakash TP 1
    • Graham MJ 1
    • Yu J 1
    • Carty R 1
    • Low A 1
    • Chappell A 1
    • Schmidt K 1
    • Zhao C 1
    • Aghajan M 1
    • Murray HF 1
    • Riney S 1
    • Booten SL 1
    • Murray SF 1
    • Gaus H 1
    • Crosby J 1
    • Lima WF 1
    • Guo S 1
    • Monia BP 1
    • Swayze EE 1
    (19 authors)
  • 2. Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA
      Authors
    • Seth PP 2
    (1 author)

ORCIDs linked to this article

Nucleic Acids Research, 03 Jul 2014, 42(13):8796-8807
https://doi.org/10.1093/nar/gku531 PMID: 24992960 PMCID: PMC4117763

This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC

Abstract 

Triantennary N-acetyl galactosamine (GalNAc, GN3: ), a high-affinity ligand for the hepatocyte-specific asialoglycoprotein receptor (ASGPR), enhances the potency of second-generation gapmer antisense oligonucleotides (ASOs) 6-10-fold in mouse liver. When combined with next-generation ASO designs comprised of short S-cEt (S-2'-O-Et-2',4'-bridged nucleic acid) gapmer ASOs, ∼ 60-fold enhancement in potency relative to the parent MOE (2'-O-methoxyethyl RNA) ASO was observed. GN3: -conjugated ASOs showed high affinity for mouse ASGPR, which results in enhanced ASO delivery to hepatocytes versus non-parenchymal cells. After internalization into cells, the GN3: -ASO conjugate is metabolized to liberate the parent ASO in the liver. No metabolism of the GN3: -ASO conjugate was detected in plasma suggesting that GN3: acts as a hepatocyte targeting prodrug that is detached from the ASO by metabolism after internalization into the liver. GalNAc conjugation also enhanced potency and duration of the effect of two ASOs targeting human apolipoprotein C-III and human transthyretin (TTR) in transgenic mice. The unconjugated ASOs are currently in late stage clinical trials for the treatment of familial chylomicronemia and TTR-mediated polyneuropathy. The ability to translate these observations in humans offers the potential to improve therapeutic index, reduce cost of therapy and support a monthly dosing schedule for therapeutic suppression of gene expression in the liver using ASOs.

Free full text 

Logo of narLink to Publisher's site
Nucleic Acids Res. 2014 Sep 1; 42(13): 8796–8807.
Published online 2014 Jul 3. https://doi.org/10.1093/nar/gku531
PMCID: PMC4117763
PMID: 24992960
NAR Breakthrough Article

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

Thazha P. Prakash, Mark J. Graham, Jinghua Yu, Rick Carty, Audrey Low, Alfred Chappell, Karsten Schmidt, Chenguang Zhao, Mariam Aghajan, Heather F. Murray, Stan Riney, Sheri L. Booten, Susan F. Murray, Hans Gaus, Jeff Crosby, Walt F. Lima, Shuling Guo, Brett P. Monia, Eric E. Swayze, and Punit P. Seth*
Author information Article notes Copyright and License information Disclaimer

Abstract

Triantennary N-acetyl galactosamine (GalNAc, GN3), a high-affinity ligand for the hepatocyte-specific asialoglycoprotein receptor (ASGPR), enhances the potency of second-generation gapmer antisense oligonucleotides (ASOs) 6–10-fold in mouse liver. When combined with next-generation ASO designs comprised of short S-cEt (S-2′-O-Et-2′,4′-bridged nucleic acid) gapmer ASOs, ~60-fold enhancement in potency relative to the parent MOE (2′-O-methoxyethyl RNA) ASO was observed. GN3-conjugated ASOs showed high affinity for mouse ASGPR, which results in enhanced ASO delivery to hepatocytes versus non-parenchymal cells. After internalization into cells, the GN3-ASO conjugate is metabolized to liberate the parent ASO in the liver. No metabolism of the GN3-ASO conjugate was detected in plasma suggesting that GN3 acts as a hepatocyte targeting prodrug that is detached from the ASO by metabolism after internalization into the liver. GalNAc conjugation also enhanced potency and duration of the effect of two ASOs targeting human apolipoprotein C-III and human transthyretin (TTR) in transgenic mice. The unconjugated ASOs are currently in late stage clinical trials for the treatment of familial chylomicronemia and TTR-mediated polyneuropathy. The ability to translate these observations in humans offers the potential to improve therapeutic index, reduce cost of therapy and support a monthly dosing schedule for therapeutic suppression of gene expression in the liver using ASOs.

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

Full text links 

Read article at publisher's site: https://doi.org/10.1093/nar/gku531

Read article for free, from open access legal sources, via Unpaywall: https://academic.oup.com/nar/article-pdf/42/13/8796/37018758/gku531.pdfUnpaywall

Citations & impact 

Impact metrics

289
Citations
Jump to Citations
1
Data citation
Jump to Data

Citations of article over time

Alternative metrics

Altmetric item for https://www.altmetric.com/details/2483740
Altmetric
Discover the attention surrounding your research
https://www.altmetric.com/details/2483740

Smart citations by scite.ai
Smart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by EuropePMC if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
Explore citation contexts and check if this article has been supported or disputed.
https://scite.ai/reports/10.1093/nar/gku531

Supporting
Mentioning
Contrasting
13
427
1

Article citations

Go to all (289) article citations

Data 

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.