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Therapeutic siRNA silencing in inflammatory monocytes in mice

2011; Nature Portfolio; Volume: 29; Issue: 11 Linguagem: Inglês

10.1038/nbt.1989

1546-1696

Florian Leuschner, Partha Dutta, Rostic Gorbatov, Tatiana I. Novobrantseva, Jessica Donahoe, Gabriel Courties, Kang Mi Lee, James I. Kim, James F. Markmann, Brett Marinelli, Peter Panizzi, Won Woo Lee, Yoshiko Iwamoto, Stuart Milstein, Hila Epstein-Barash, William Cantley, Jamie Wong, Virna Cortez‐Retamozo, Andita Newton, Kevin T. Love, Peter Libby, Mikaël J. Pittet, Filip K. Świrski, Victor Koteliansky, Róbert Langer, Ralph Weissleder, Daniel G. Anderson, Matthias Nahrendorf,

Chemokine receptors and signaling

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.