title: Therapeutic siRNA silencing in inflammatory monocytes in mice.
abstract: 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.
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Florian
authors: F
authors: Leuschner
authors: Partha
authors: P
authors: Dutta
authors: Rostic
authors: R
authors: Gorbatov
authors: Tatiana I
authors: TI
authors: Novobrantseva
authors: Jessica S
authors: JS
authors: Donahoe
authors: Gabriel
authors: G
authors: Courties
authors: Kang Mi
authors: KM
authors: Lee
authors: James I
authors: JI
authors: Kim
authors: James F
authors: JF
authors: Markmann
authors: Brett
authors: B
authors: Marinelli
authors: Peter
authors: P
authors: Panizzi
authors: Won Woo
authors: WW
authors: Lee
authors: Yoshiko
authors: Y
authors: Iwamoto
authors: Stuart
authors: S
authors: Milstein
authors: Hila
authors: H
authors: Epstein-Barash
authors: William
authors: W
authors: Cantley
authors: Jamie
authors: J
authors: Wong
authors: Virna
authors: V
authors: Cortez-Retamozo
authors: Andita
authors: A
authors: Newton
authors: Kevin
authors: K
authors: Love
authors: Peter
authors: P
authors: Libby
authors: Mikael J
authors: MJ
authors: Pittet
authors: Filip K
authors: FK
authors: Swirski
authors: Victor
authors: V
authors: Koteliansky
authors: Robert
authors: R
authors: Langer
authors: Ralph
authors: R
authors: Weissleder
authors: Daniel G
authors: DG
authors: Anderson
authors: Matthias
authors: M
authors: Nahrendorf
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000628:therapy; D001786:Blood Glucose; D003920:Diabetes Mellitus / Q000601:surgery / Q000628:therapy; D004195:Disease Models, Animal; D020868:Gene Silencing; D006085:Graft Survival / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000628:therapy*; D016381:Islets of Langerhans Transplantation; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D009203:Myocardial Infarction / Q000517:prevention & control / Q000628:therapy; D053758:Nanoparticles / Q000737:chemistry; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D001786:Blood Glucose; C515335:Ccr2 protein, mouse; D034741:RNA, Small Interfering; D054390:Receptors, CCR2