Article

Therapeutic siRNA silencing in inflammatory monocytes in mice.

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Nature Biotechnology (Impact Factor: 32.44). 11/2011; 29(11):1005-10. DOI: 10.1038/nbt.1989
Source: PubMed

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.

1 Bookmark
 · 
238 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Monocytes and macrophages have crucial and distinct roles in tissue homeostasis and immunity, but they also contribute to a broad spectrum of pathologies and are thus attractive therapeutic targets. Potential intervention strategies that aim to manipulate these cells will require an in-depth understanding of their origins and the mechanisms that ensure their homeostasis. Recent evidence shows that monocytes do not substantially contribute to most tissue macrophage populations in the steady state or during certain types of inflammation. Rather, most tissue macrophage populations in mice are derived from embryonic precursors, are seeded before birth and can maintain themselves in adults by self-renewal. In this Review, we discuss the evidence that has dramatically changed our understanding of monocyte and macrophage development, and the maintenance of these cells in the steady state.
    Nature reviews. Immunology. 05/2014; 14(6):392-404.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Inflammation is an immune response that marks several pathophysiological conditions in our body. Though adaptive immune cells play a major role in the progression of the disease, components of innate immune system, mainly monocytes and macrophages play the central role in onset of inflammation. Tissue-associated macrophages are widely distributed in the body showing tremendous anatomical and functional diversity and are actively involved in maintaining the homeostasis. They exhibit different phenotypes depending on their residing tissue microenvironment and the two major functional phenotypes are classically activated M1 phenotype showing pro-inflammatory characteristics and alternatively activated M2 phenotype demonstrating anti-inflammatory nature. Several cytokines, chemokines and other regulatory mediators delicately govern the balance of the two phenotypes in a tissue. This balance, however, is subverted during infection, injury or autoimmune response leading to increased population of M1 phenotype and subsequent chronic inflammatory disease states. This review underlines the role of macrophages in inflammatory diseases with an insight on potential molecular targets for nucleic acid therapy. Finally, some recent nanotechnology-based approaches to devise macrophage-specific targeted therapy have been highlighted.
    Journal of Controlled Release 04/2014; · 7.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Monocytes and macrophages are heterogeneous populations of effector cells in the innate immune system. Once thought to be obligatory precursors for macrophages, monocytes are now known to have several distinct sub-populations and their own independent functions. This separation of the two lineages has opened new therapeutic avenues in inflammation and created new technologies targeting the mononuclear phagocyte system (MPS). Areas covered: A search of Google Patents and PatentScope has revealed numerous patents targeting monocytes and macrophages. This review will focus on seven patents from 2009 to 2013, utilizing autologous monocyte and macrophage adoptive transfer, genetic manipulation of the MPS, therapeutic nanoparticles and liposomes or combinations of these strategies. Patents that target monocyte recruitment are also briefly reviewed. Expert opinion: While monocyte and macrophage targeting has yielded some promising results in animal models, these often fail to translate well to successful clinical trials. The paradigm of how cells in the MPS interact and evolve is constantly being updated, and caution must be exercised in developing immunomodulatory agents until this relationship is better understood.
    Expert Opinion on Therapeutic Patents 04/2014; · 3.53 Impact Factor

Full-text (2 Sources)

Download
161 Downloads
Available from
Jun 10, 2014