TY - JOUR
T1 - Therapeutic siRNA silencing in inflammatory monocytes in mice
AU - Leuschner, Florian
AU - Dutta, Partha
AU - Gorbatov, Rostic
AU - Novobrantseva, Tatiana I.
AU - Donahoe, Jessica S.
AU - Courties, Gabriel
AU - Lee, Kang Mi
AU - Kim, James I.
AU - Markmann, James F.
AU - Marinelli, Brett
AU - Panizzi, Peter
AU - Lee, Won Woo
AU - Iwamoto, Yoshiko
AU - Milstein, Stuart
AU - Epstein-Barash, Hila
AU - Cantley, William
AU - Wong, Jamie
AU - Cortez-Retamozo, Virna
AU - Newton, Andita
AU - Love, Kevin
AU - Libby, Peter
AU - Pittet, Mikael J.
AU - Swirski, Filip K.
AU - Koteliansky, Victor
AU - Langer, Robert
AU - Weissleder, Ralph
AU - Anderson, Daniel G.
AU - Nahrendorf, Matthias
N1 - Funding Information:
The authors thank M. Waring, A. Chicoine and the Ragon Institute (MGH) for cell sorting, the CSB Mouse Imaging Program (P. Waterman, B. Sena) and B. Bettencourt for designing initial sets of siRNA. We acknowledge the small, medium and large scale RNA synthesis groups at Alnylam as well as analytical, duplex annealing and QC groups for synthesizing and characterizing RNAs. This work was funded in part by grants from the US National Institutes of Health R01-HL096576, R01-HL095629 (M.N.); R01-EB006432, T32-CA79443, U24-CA92782, P50-CA86355, HHSN268201000044C (R.W.); R01-CA132091, R01-CA115527, R37-EB000244 (R.L.); Deutsche Herzstiftung (F.L.); and the SNUBH Research Fund 02-2007-013 (W.W.L.).
PY - 2011/11
Y1 - 2011/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/80155200721
U2 - 10.1038/nbt.1989
DO - 10.1038/nbt.1989
M3 - Article
C2 - 21983520
AN - SCOPUS:80155200721
SN - 1087-0156
VL - 29
SP - 1005
EP - 1010
JO - Nature Biotechnology
JF - Nature Biotechnology
IS - 11
ER -