Intrabody tissue-specific delivery of antisense conjugates in animals: Ligand-linker-antisense oligomer conjugates

Duff, R. Joel; Deamond, Scott F.; Roby, Clinton D.; Zhou, Yuanzhong; Ts’o, Paul O. P.

doi:10.1016/s0076-6879(00)13019-8

Cited by 25 publications

(25 citation statements)

References 29 publications

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“…Similarly, when a PS oligomer was conjugated to this glycotripeptide, there was sequencespecific suppression of the integrated HBV viral expression in hepatoma cells (greater than 90% inhibition) in a dose-dependent concentration range of 1-20 μM of ODNs. (163) Galactose is the ligand for the asialoglycoprotein receptor, which is expressed on the surface of liver parenchymal cells. Biessen et al (164,165) constructed four molecules of galactoses on a oligolysine (N2-(N2-(N2, N6-…”

Section: Conjugation Of Lipophilic Molecules-becausementioning

confidence: 99%

Gene Modulation for Treating Liver Fibrosis

Cheng

Mahato

2007

Crit Rev Ther Drug Carrier Syst

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Despite tremendous progress in our understanding of fibrogenesis, injury stimuli process, inflammation, and hepatic stellate cells (HSC) activation, there is still no standard treatment for liver fibrosis. Delivery of small molecular weight drug, proteins and nucleic acids to specific liver cell types remains a challenge due to the overexpression of extra cellular matrix (ECM) and consequent closure of sinusoidal gaps. In addition, activation of HSCs and subsequent release of inflammatory cytokines and infiltration of immune cells are other major obstacles to the treatment of liver fibrosis. To overcome these barriers, different therapeutic approaches are being investigated. Among them, modulation of certain aberrant protein production is quite promising for treating liver fibrosis. In this review, we will describe the mechanism of antisense, antigene and RNA interference (RNAi) therapies, and will discuss how the backbone modification of oligonucleotides affects their in vivo stability, biodistribution and bioactivity. Strategies for delivering these nucleic acids to specific cell types will be discussed. This review will critically address various insights developed in each individual strategy and for multipronged approaches, which will be helpful in achieving better outcomes.

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Section: Conjugation Of Lipophilic Molecules-becausementioning

confidence: 99%

Gene Modulation for Treating Liver Fibrosis

Cheng

Mahato

2007

Crit Rev Ther Drug Carrier Syst

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“…Galactose and GalNAc ligands display maximum affinity to ASGR, and numerous natural and synthetic sugar-based ligands have been described and investigated for their ASGR binding activity (11). For example, a number of biomolecules such as modified lipoprotein particles (12), genes (13) and chemically modified oligonucleotides (14–18) have been studied for targeted delivery via ASGR in animal models.…”

Section: Introductionmentioning

confidence: 99%

Characterizing the effect of GalNAc and phosphorothioate backbone on binding of antisense oligonucleotides to the asialoglycoprotein receptor

Schmidt

Prakash

Donner

et al. 2017

Nucleic Acids Research

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Targeted delivery of antisense oligonucleotides (ASO) to hepatocytes via the asialoglycoprotein receptor (ASGR) has improved the potency of ASO drugs ∼30-fold in the clinic (1). In order to fully characterize the effect of GalNAc valency, oligonucleotide length, flexibility and chemical composition on ASGR binding, we tested and validated a fluorescence polarization competition binding assay. The ASGR binding, and in vitro and in vivo activities of 1, 2 and 3 GalNAc conjugated single stranded and duplexed ASOs were studied. Two and three GalNAc conjugated single stranded ASOs bind the ASGR with the strongest affinity and display optimal in vitro and in vivo activities. 1 GalNAc conjugated ASOs showed 10-fold reduced ASGR binding affinity relative to three GalNAc ASOs but only 2-fold reduced activity in mice. An unexpected observation was that the ASGR also appears to play a role in the uptake of unconjugated phosphorothioate modified ASOs in the liver as evidenced by the loss of activity of GalNAc conjugated and unconjugated ASOs in ASGR knockout mice. Our results provide insights into how backbone charge and chemical composition assist in the binding and internalization of highly polar anionic single stranded oligonucleotides into cells and tissues.

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“…Subsequent studies of this glycoconjugate in mice also showed that hepatic uptake of this conjugate was 70% of the injected dose (517). In another study, when a PS-ODN was conjugated to this ligand, >90% inhibition of the integrated HBV via expression in hepatoma cells could be achieved (518).…”

Section: Carbohydrate Conjugates For Targeted Delivery-delivery Of Odmentioning

confidence: 94%

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

Houssein

Mahato

2007

Oligonucleotides

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Liver fibrosis results from chronic liver injury due to hepatitis B and C, excessive alcohol ingestion, and metal ion overload. Fibrosis culminates in cirrhosis and results in liver failure. Therefore, a potent antifibrotic therapy is in urgent need to reverse scarring and eliminate progression to cirrhosis. Although activated hepatic stellate cells (HSCs) remains the principle cell type responsible for liver fibrosis, perivascular fibroblasts of portal and central veins as well as periductular fibroblasts are other sources of fibrogenic cells. This review will critically discuss various treatment strategies for liver fibrosis, including prevention of liver injury, reduction of inflammation, inhibition of HSC activation, degradation of scar matrix, and inhibition of aberrant collagen synthesis. Oligonucleotides (ODNs) are short, single-stranded nucleic acids, which disrupt expression of target protein by binding to complementary mRNA or forming triplex with genomic DNA. Triplex forming oligonucleotides (TFOs) provide an attractive strategy for treating liver fibrosis. A series of TFOs have been developed for inhibiting the transcription of α1(I) collagen gene, which opens a new area for antifibrotic drugs. There will be in depth discussion on the use of TFOs and how different bioconjugation strategies can be utilized for their site-specific delivery to HSCs or hepatocytes for enhanced antifibrotic activities. Various insights developed in individual strategy and the need for multipronged approaches will also be discussed.

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Intrabody tissue-specific delivery of antisense conjugates in animals: Ligand-linker-antisense oligomer conjugates

Cited by 25 publications

References 29 publications

Gene Modulation for Treating Liver Fibrosis

Gene Modulation for Treating Liver Fibrosis

Characterizing the effect of GalNAc and phosphorothioate backbone on binding of antisense oligonucleotides to the asialoglycoprotein receptor

Bioconjugation of Oligonucleotides for Treating Liver Fibrosis

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