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: Florian Leuschner, Partha Dutta, Rostic Gorbatov, Tatiana I Novobrantseva, Jessica S 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 Love, Peter Libby, Mikael J Pittet, Filip K Swirski, Victor Koteliansky, Robert Langer, Ralph Weissleder, Daniel G Anderson, Matthias Nahrendorf
• Journal: Nature biotechnology (Nat Biotechnol) Vol. 29 Issue 11 Pg. 1005-10 (Oct 09 2011) ISSN: 1546-1696 [Electronic] United States
• PMID: 21983520 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Ccr2 protein, mouse
• RNA, Small Interfering
• Receptors, CCR2

Topics

• Animals
• Atherosclerosis (therapy)
• Blood Glucose
• Diabetes Mellitus (surgery, therapy)
• Disease Models, Animal
• Gene Silencing
• Graft Survival (genetics)
• Humans
• Inflammation (therapy)
• Islets of Langerhans Transplantation
• Macrophages (drug effects)
• Mice
• Mice, Inbred C57BL
• Monocytes (metabolism)
• Myocardial Infarction (prevention & control, therapy)
• Nanoparticles (chemistry)
• RNA, Small Interfering (therapeutic use)
• Receptors, CCR2 (antagonists & inhibitors, genetics)