Gene Knockdown by EpCAM Aptamer–siRNA Chimeras Suppresses Epithelial Breast Cancers and Their Tumor-Initiating Cells

Gilboa-Geffen, Adi; Hamar, Péter; Le, Minh Vuong; Wheeler, Lee Adam; Trifonova, Radiana; Petrocca, Fabio; Wittrup, Anders; Lieberman, Judy

doi:10.1158/1535-7163.mct-15-0201-t

Cited by 68 publications

(45 citation statements)

References 48 publications

(70 reference statements)

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“…Thus, this tool could also be used to study the role of host genes in SIV transmission in macaques, where gene knockout is not easy. We have recently found that EpCAM-AsiCs given subcutaneously can silence gene expression in EpCAM+ cells distributed at distal sites throughout the mouse (Gilboa-Geffen et al, 2015). Preliminary studies of subcutaneous injection of CD4-AsiCs in humanized mice also show strong knockdown (~80%) in CD4+ T cells in local lymph nodes, as well as in the spleen and distal lymph nodes.…”

Section: Discussionmentioning

confidence: 99%

TREX1 Knockdown Induces an Interferon Response to HIV that Delays Viral Infection in Humanized Mice

et al. 2016

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Summary Despite their antiviral effect, the in vivo effect of interferons on HIV transmission is difficult to predict, because interferons also activate and recruit HIV-susceptible cells to sites of infection. HIV does not normally induce Type I interferons in infected cells, but does if TREX1 is knocked down. Here we investigated the effect of topical TREX1 knockdown and local interferon production on HIV transmission in human cervicovaginal explants and humanized mice. In explants in which TREX1 was knocked down, HIV induced interferons, which blocked infection. In humanized mice, even though TREX1 knockdown increased infiltrating immune cells, it delayed viral replication for 3–4 weeks. Similarly intravaginal application of Type I interferons the day before HIV infection induced interferon responsive genes, reduced inflammation and decreased viral replication. However, intravenous interferon enhanced inflammation and infection. Thus, in models of human sexual transmission, a localized interferon response inhibits HIV transmission, but systemic interferons do not.

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Section: Discussionmentioning

confidence: 99%

TREX1 Knockdown Induces an Interferon Response to HIV that Delays Viral Infection in Humanized Mice

et al. 2016

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“…These are taken up by receptor-mediated endocytosis and cleaved by Dicer to liberate an active siRNA. Recent work with breast cancer homing epithelial cell adhesion molecule (EpCAM) aptamer–siRNA chimaeras suggests that, like GalNAc conjugates, they concentrate in targeted tissues after subcutaneous injection 95 . Application of improved chemistries for nuclease stability and novel endosomal escape strategies may further improve this versatile siRNA delivery platform.…”

Section: Moving Beyond the Livermentioning

confidence: 99%

Knocking down disease: a progress report on siRNA therapeutics

2015

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Small interfering RNAs (siRNAs), which downregulate gene expression guided by sequence complementarity, can be used therapeutically to block the synthesis of disease-causing proteins. The main obstacle to siRNA drugs — their delivery into the target cell cytosol — has been overcome to allow suppression of liver gene expression. Here, we review the results of recent clinical trials of siRNA therapeutics, which show efficient and durable gene knockdown in the liver, with signs of promising clinical outcomes and little toxicity. We also discuss the barriers to more widespread applications that target tissues besides the liver and the most promising avenues to overcome them.

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“…We recently found that subcutaneous administration of naked aptamer-siRNAs (AsiCs) targeting CD4 or an epithelial cancer receptor concentrate in aptamer-targeted cells, leading to systemic gene knockdown (i.e., the CD4-AsiC causes efficient knockdown in the spleen and distal lymph nodes) [49] (and J.L., unpublished). Subcutaneous administration of aptamers and aptamer conjugates should provide a good solution to the poor pharmacological properties of intravenously injected small RNAs, enabling aptamers to substitute for antibodies in many in vivo applications.…”

Section: Aptamers Vs Antibodiesmentioning

confidence: 99%

Manipulating the in vivo immune response by targeted gene knockdown

Lieberman

2015

Current Opinion in Immunology

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Aptamers, nucleic acids selected for high affinity binding to proteins, can be used to activate or antagonize immune mediators or receptors in a location and cell-type specific manner and to enhance antigen presentation. They can also be linked to other molecules (other aptamers, siRNAs or miRNAs, proteins, toxins) to produce multifunctional compounds for targeted immune modulation in vivo. Aptamer-siRNA chimeras (AsiCs) that induce efficient cell-specific knockdown in immune cells in vitro and in vivo can be used as an immunological research tool or potentially as an immunomodulating therapeutic.

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Gene Knockdown by EpCAM Aptamer–siRNA Chimeras Suppresses Epithelial Breast Cancers and Their Tumor-Initiating Cells

Cited by 68 publications

References 48 publications

TREX1 Knockdown Induces an Interferon Response to HIV that Delays Viral Infection in Humanized Mice

TREX1 Knockdown Induces an Interferon Response to HIV that Delays Viral Infection in Humanized Mice

Knocking down disease: a progress report on siRNA therapeutics

Manipulating the in vivo immune response by targeted gene knockdown

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