A novel siRNA-lipoplex technology for RNA interference in the mouse vascular endothelium

Santel, Ansgar; Aleku, Manuela; Keil, Oliver; Endruschat, Jens; Esche, V; Fisch, Gerald; Dames, Sibylle; Löffler, Kathrin; Fechtner, Melanie; Arnold, W; Giese, Klaus; Klippel, Anke; Kaufmann, Jörg

doi:10.1038/sj.gt.3302777

Cited by 337 publications

(312 citation statements)

References 55 publications

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“…However, systemic delivery to many tissues, including liver, requires a vehicle to provide protection and transport of siRNA to the cells of interest. To this end, a variety of carrier systems utilizing both natural and synthetic materials have been developed (8)(9)(10)(11)(12)(13)(14)(15). Cationic lipids represent one of the most well-studied classes of synthetic materials for siRNA delivery.…”

mentioning

confidence: 99%

Lipid-like materials for low-dose, in vivo gene silencing

Love

Mahon

Levins

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

817

803

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Significant effort has been applied to discover and develop vehicles which can guide small interfering RNAs (siRNA) through the many barriers guarding the interior of target cells. While studies have demonstrated the potential of gene silencing in vivo, improvements in delivery efficacy are required to fulfill the broadest potential of RNA interference therapeutics. Through the combinatorial synthesis and screening of a different class of materials, a formulation has been identified that enables siRNA-directed liver gene silencing in mice at doses below 0.01 mg/kg. This formulation was also shown to specifically inhibit expression of five hepatic genes simultaneously, after a single injection. The potential of this formulation was further validated in nonhuman primates, where high levels of knockdown of the clinically relevant gene transthyretin was observed at doses as low as 0.03 mg/kg. To our knowledge, this formulation facilitates gene silencing at orders-of-magnitude lower doses than required by any previously described siRNA liver delivery system.

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mentioning

confidence: 99%

Lipid-like materials for low-dose, in vivo gene silencing

Love

Mahon

Levins

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

817

803

View full text Add to dashboard Cite

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“…The sense strand was 5′-auaucugggcaaaugaugg-3′, and the antisense strand was 5′-ccaucauuugcccagauau-3′, with the underlined nucleotides bearing 2′-Omethyl modification (42). Animals were euthanized by exsanguination under anesthesia, followed by rapid collection of organs into liquid nitrogen for further analysis.…”

Section: Methodsmentioning

confidence: 99%

“…To achieve acute Tie2 knock down in mice, lipoplexed siTie2 or control siRNA was administered via intravenous injection as described previously (42). The sense strand was 5′-auaucugggcaaaugaugg-3′, and the antisense strand was 5′-ccaucauuugcccagauau-3′, with the underlined nucleotides bearing 2′-Omethyl modification (42).…”

Section: Methodsmentioning

confidence: 99%

Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

Ghosh

David

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Ligands of the endothelial-enriched tunica interna endothelial cell kinase 2 (Tie2) are markedly imbalanced in severe infections associated with vascular leakage, yet regulation of the receptor itself has been understudied in this context. Here, we show that TIE2 gene expression may constitute a novel vascular barrier control mechanism in diverse infections. Tie2 expression declined rapidly in wide-ranging models of leak-associated infections, including anthrax, influenza, malaria, and sepsis. Forced Tie2 suppression sufficed to attenuate barrier function and sensitize endothelium to permeability mediators. Rapid reduction of pulmonary Tie2 in otherwise healthy animals attenuated downstream kinase signaling to the barrier effector vascular endothelial (VE)-cadherin and induced vascular leakage. Compared with wild-type littermates, mice possessing one allele of Tie2 suffered more severe vascular leakage and higher mortality in two different sepsis models. Common genetic variants that influence TIE2 expression were then sought in the HapMap3 cohort. Remarkably, each of the three strongest predicted cis-acting SNPs in HapMap3 was also associated with the risk of acute respiratory distress syndrome (ARDS) in an intensive care unit cohort of 1,614 subjects. The haplotype associated with the highest TIE2 expression conferred a 28% reduction in the risk of ARDS independent of other major clinical variables, including disease severity. In contrast, the most common haplotype was associated with both the lowest TIE2 expression and 31% higher ARDS risk. Together, the results implicate common genetic variation at the TIE2 locus as a determinant of vascular leak-related clinical outcomes from common infections, suggesting new tools to identify individuals at unusual risk for deleterious complications of infection.Tie2 | endothelium | infection | angiopoietin | permeability

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“…None of the T and B lymphocytes in the joints showed positive staining for the siRNA (data not shown). As systemically administered siRNAs might also be taken up by endothelial cells (ECs), 28 known to have a high capacity for antigen uptake and processing, the siRNA fluorescence was also investigated in CD146-positive cells from the spleen and liver ( Figure 2F). Two days after injection, up to 3% of the ECs from the spleen and 10% of the liver sinusoidal endothelial cells (LSECs) had taken up the siRNAs, the levels decreasing rapidly thereafter.…”

Section: Mps-specific Tak1 Rnai For Immunomodulation 3507mentioning

confidence: 99%