Therapeutic siRNA silencing in inflammatory monocytes in mice

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 LovePeter Libby, Mikael J. Pittet, Filip K. Swirski, Victor Koteliansky, Robert Langer, Ralph Weissleder, Daniel G. Anderson, Matthias Nahrendorf

Research output: Contribution to journalArticle

425 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1005-1010
Number of pages6
JournalNature Biotechnology
Volume29
Issue number11
DOIs
StatePublished - 1 Nov 2011

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Small Interfering RNA
Tumors
Monocytes
Macrophages
Chemokine Receptors
Immune system
RNA
Lipids
Bone
Blood
Tissue
Nanoparticles
Degradation
Islets of Langerhans Transplantation
Messenger RNA
Coronary Occlusion
RNA Stability
Atherosclerotic Plaques
Therapeutics
Tumor Burden

Cite this

Leuschner, F., Dutta, P., Gorbatov, R., Novobrantseva, T. I., Donahoe, J. S., Courties, G., ... Nahrendorf, M. (2011). Therapeutic siRNA silencing in inflammatory monocytes in mice. Nature Biotechnology, 29(11), 1005-1010. https://doi.org/10.1038/nbt.1989
Leuschner, Florian ; Dutta, Partha ; Gorbatov, Rostic ; Novobrantseva, Tatiana I. ; Donahoe, Jessica S. ; Courties, Gabriel ; Lee, Kang Mi ; Kim, James I. ; Markmann, James F. ; Marinelli, Brett ; Panizzi, Peter ; Lee, Won Woo ; Iwamoto, Yoshiko ; Milstein, Stuart ; Epstein-Barash, Hila ; Cantley, William ; Wong, Jamie ; Cortez-Retamozo, Virna ; Newton, Andita ; Love, Kevin ; Libby, Peter ; Pittet, Mikael J. ; Swirski, Filip K. ; Koteliansky, Victor ; Langer, Robert ; Weissleder, Ralph ; Anderson, Daniel G. ; Nahrendorf, Matthias. / Therapeutic siRNA silencing in inflammatory monocytes in mice. In: Nature Biotechnology. 2011 ; Vol. 29, No. 11. pp. 1005-1010.
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Leuschner, F, Dutta, P, Gorbatov, R, Novobrantseva, TI, Donahoe, JS, Courties, G, Lee, KM, Kim, JI, Markmann, JF, Marinelli, B, Panizzi, P, Lee, WW, Iwamoto, Y, Milstein, S, Epstein-Barash, H, Cantley, W, Wong, J, Cortez-Retamozo, V, Newton, A, Love, K, Libby, P, Pittet, MJ, Swirski, FK, Koteliansky, V, Langer, R, Weissleder, R, Anderson, DG & Nahrendorf, M 2011, 'Therapeutic siRNA silencing in inflammatory monocytes in mice', Nature Biotechnology, vol. 29, no. 11, pp. 1005-1010. https://doi.org/10.1038/nbt.1989

Therapeutic siRNA silencing in inflammatory monocytes in mice. / Leuschner, Florian; Dutta, Partha; Gorbatov, Rostic; Novobrantseva, Tatiana I.; Donahoe, Jessica S.; Courties, Gabriel; Lee, Kang Mi; Kim, James I.; Markmann, James F.; Marinelli, Brett; Panizzi, Peter; Lee, Won Woo; Iwamoto, Yoshiko; Milstein, Stuart; Epstein-Barash, Hila; Cantley, William; Wong, Jamie; Cortez-Retamozo, Virna; Newton, Andita; Love, Kevin; Libby, Peter; Pittet, Mikael J.; Swirski, Filip K.; Koteliansky, Victor; Langer, Robert; Weissleder, Ralph; Anderson, Daniel G.; Nahrendorf, Matthias.

In: Nature Biotechnology, Vol. 29, No. 11, 01.11.2011, p. 1005-1010.

Research output: Contribution to journalArticle

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AU - Kim, James I.

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AU - Lee, Won Woo

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AU - Wong, Jamie

AU - Cortez-Retamozo, Virna

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AU - Libby, Peter

AU - Pittet, Mikael J.

AU - Swirski, Filip K.

AU - Koteliansky, Victor

AU - Langer, Robert

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Leuschner F, Dutta P, Gorbatov R, Novobrantseva TI, Donahoe JS, Courties G et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nature Biotechnology. 2011 Nov 1;29(11):1005-1010. https://doi.org/10.1038/nbt.1989