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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, [......],
Andita Newton,
Kevin Love,
Peter Libby,
Mikael J Pittet,
Filip K Swirski,
Victor Koteliansky,
Robert Langer,
Ralph Weissleder,
Daniel G Anderson,
Matthias Nahrendorf
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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.
Nature Biotechnology 11/2011; 29(11):1005-10. · 29.50 Impact Factor
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Kiran Musunuru,
Alanna Strong,
Maria Frank-Kamenetsky,
Noemi E Lee,
Tim Ahfeldt,
Katherine V Sachs,
Xiaoyu Li,
Hui Li,
Nicolas Kuperwasser,
Vera M Ruda, [......],
Timothy Racie,
Kenechi G Ejebe,
Marju Orho-Melander,
Olle Melander,
Victor Koteliansky,
Kevin Fitzgerald,
Ronald M Krauss,
Chad A Cowan,
Sekar Kathiresan,
Daniel J Rader
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ABSTRACT: Recent genome-wide association studies (GWASs) have identified a locus on chromosome 1p13 strongly associated with both plasma low-density lipoprotein cholesterol (LDL-C) and myocardial infarction (MI) in humans. Here we show through a series of studies in human cohorts and human-derived hepatocytes that a common noncoding polymorphism at the 1p13 locus, rs12740374, creates a C/EBP (CCAAT/enhancer binding protein) transcription factor binding site and alters the hepatic expression of the SORT1 gene. With small interfering RNA (siRNA) knockdown and viral overexpression in mouse liver, we demonstrate that Sort1 alters plasma LDL-C and very low-density lipoprotein (VLDL) particle levels by modulating hepatic VLDL secretion. Thus, we provide functional evidence for a novel regulatory pathway for lipoprotein metabolism and suggest that modulation of this pathway may alter risk for MI in humans. We also demonstrate that common noncoding DNA variants identified by GWASs can directly contribute to clinical phenotypes.
Nature 08/2010; 466(7307):714-9. · 36.28 Impact Factor
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Kevin T Love,
Kerry P Mahon,
Christopher G Levins,
Kathryn A Whitehead,
William Querbes,
J Robert Dorkin,
June Qin, William Cantley,
Liu Liang Qin,
Timothy Racie,
Maria Frank-Kamenetsky,
Ka Ning Yip,
Rene Alvarez,
Dinah W Y Sah,
Antonin de Fougerolles,
Kevin Fitzgerald,
Victor Koteliansky,
Akin Akinc,
Robert Langer,
Daniel G Anderson
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ABSTRACT: Significant effort has been applied to discover and develop vehicles which can guide small interfering RNAs (siRNA) through the many barriers guarding the interior of target cells. While studies have demonstrated the potential of gene silencing in vivo, improvements in delivery efficacy are required to fulfill the broadest potential of RNA interference therapeutics. Through the combinatorial synthesis and screening of a different class of materials, a formulation has been identified that enables siRNA-directed liver gene silencing in mice at doses below 0.01 mg/kg. This formulation was also shown to specifically inhibit expression of five hepatic genes simultaneously, after a single injection. The potential of this formulation was further validated in nonhuman primates, where high levels of knockdown of the clinically relevant gene transthyretin was observed at doses as low as 0.03 mg/kg. To our knowledge, this formulation facilitates gene silencing at orders-of-magnitude lower doses than required by any previously described siRNA liver delivery system.
Proceedings of the National Academy of Sciences 02/2010; 107(5):1864-9. · 9.68 Impact Factor
