Therapeutic siRNA silencing in inflammatory monocytes

By F. Leuschner, Partha Dutta, Rostic Gorbatov, T. Novobrantseva, J. Sullivan, G. Courties, K. Lee, James I. Kim, J. Markmann, Brett Marinelli and 18 more. Nature Biotechnology, 2011

835 citations recorded by the source corpus.

Excessive and prolonged activity of inflammatory monocytes is a hallmark of many diseases with an inflammatory component. In such conditions, precise targeting of these cells could be therapeutically beneficial while sparing many essential functions of the innate immune system, thus limiting unwanted effects. Inflammatory monocytes—but not the noninflammatory subset—depend on the chemokine receptor CCR2 for localization to injured tissue. Here we present an optimized lipid nanoparticle and a CCR2-silencing short interfering RNA that, when administered systemically in mice, show rapid blood clearance, accumulate in spleen and bone marrow, and localize to monocytes. Efficient degradation of CCR2 mRNA in monocytes prevents their accumulation in sites of inflammation. Specifically, the treatment attenuates their number in atherosclerotic plaques, reduces infarct size after coronary artery occlusion, prolongs normoglycemia in diabetic mice after pancreatic islet transplantation, and results in reduced tumor volumes and lower numbers of tumor-associated macrophages.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/40d4ade4e4498f03c66eaff06a0d40fd8f5a0bc9

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Citations in the corpus

Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology (2017, background): “mation, systemic delivery of optimized lipid nanoparticles containing a CCR2-silencing short interfering RNA (siRNA) efficiently degraded CCR2mRNA and impaired IMM recruitment to sites of inflammation thus resulting in improved disease outcome [129, 130].”
Origins of tumor-associated macrophages and neutrophils (2012, methodology): “To test whether CCR2 controlled spleenderived TAM accumulation, we used a lipid nanoparticle that contains short interfering (si) CCR2 RNA sequences and that selectively silences CCR2 expression in splenic Ly-6C (CCR2) monocytes (23).”
Macrophage Phenotype and Function in Different Stages of Atherosclerosis (2016, neutral): “short interfering RNA that prevents monocyte recruitment to lesions.(140) Development of nanoparticles or other treatment”
Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression and improves chemotherapeutic responses (2012, background): “suggested that CCR2 mediates the trafficking of circulating Ly6CHiCCR2þCX3CR1Lo inflammatory monocytes to target tissues (38, 39), whereas CSF1R is more likely involved in maturation and/or survival of these cells at inflamed sites.”
Molecularly Self-Assembled Nucleic Acid Nanoparticles for Targeted In Vivo siRNA Delivery (2012, methodology): “…ONPs with folate ligands (3 nmol of siRNA, ∼ 2.0 mg/kg) (6 FA ligands per ONP) were systemically delivered via tail-vein injection and the in vivo behavior was quantitatively measured over the course of 24 h by fluorescence molecular tomography fused with computed tomography (FMT-CT) 24,25 .”