Systemic RNAi-mediated Gene Silencing in Nonhuman Primate and Rodent Myeloid Cells

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Systemic RNAi-mediated Gene Silencing in Nonhuman Primate and Rodent Myeloid Cells

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Title: Systemic RNAi-mediated Gene Silencing in Nonhuman Primate and Rodent Myeloid Cells
Author: Novobrantseva, Tatiana I; Borodovsky, Anna; Wong, Jamie; Klebanov, Boris; Zafari, Mohammad; Yucius, Kristina; Querbes, William; Ge, Pei; Milstein, Stuart; Speciner, Lauren; Duncan, Rick; Barros, Scott; Basha, Genc; Cullis, Pieter; Akinc, Akin; Donahoe, Jessica S; Narayanannair Jayaprakash, K; Jayaraman, Muthusamy; Bogorad, Roman L; Love, Kevin; Whitehead, Katie; Levins, Chris; Manoharan, Muthiah; de Fougerolles, Antonin; Koteliansky, Victor; Ruda, Vera M.; Swirski, Filip K.; Weissleder, Ralph; Langer, Robert S.; Anderson, Daniel Griffith; Nahrendorf, Matthias

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Citation: Novobrantseva, Tatiana I, Anna Borodovsky, Jamie Wong, Boris Klebanov, Mohammad Zafari, Kristina Yucius, William Querbes, Pei Ge, Vera M Ruda, Stuart Milstein, Lauren Speciner, Rick Duncan, Scott Barros, Genc Basha, Pieter Cullis, Akin Akinc, Jessica S Donahoe, K Narayanannair Jayaprakash, Muthusamy Jayaraman, Roman L Bogorad, Kevin Love, Katie Whitehead, Chris Levins, Muthiah Manoharan, Filip K Swirski, Ralph Weissleder, Robert Langer, Daniel G Anderson, Antonin de Fougerolles, Matthias Nahrendorf, and Victor Koteliansky. 2012. Systemic RNAi-mediated gene silencing in nonhuman primate and rodent myeloid cells. Molecular Therapy-Nucleic Acids 1(1): e4.
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Abstract: Leukocytes are central regulators of inflammation and the target cells of therapies for key diseases, including autoimmune, cardiovascular, and malignant disorders. Efficient in vivo delivery of small interfering RNA (siRNA) to immune cells could thus enable novel treatment strategies with broad applicability. In this report, we develop systemic delivery methods of siRNA encapsulated in lipid nanoparticles (LNP) for durable and potent in vivo RNA interference (RNAi)-mediated silencing in myeloid cells. This work provides the first demonstration of siRNA-mediated silencing in myeloid cell types of nonhuman primates (NHPs) and establishes the feasibility of targeting multiple gene targets in rodent myeloid cells. The therapeutic potential of these formulations was demonstrated using siRNA targeting tumor necrosis factor-α (TNFα) which induced substantial attenuation of disease progression comparable to a potent antibody treatment in a mouse model of rheumatoid arthritis (RA). In summary, we demonstrate a broadly applicable and therapeutically relevant platform for silencing disease genes in immune cells.
Published Version: doi:10.1038/mtna.2011.3
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