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Science 319 (5863): 627-630

Copyright © 2008 by the American Association for the Advancement of Science

Systemic Leukocyte-Directed siRNA Delivery Revealing Cyclin D1 as an Anti-Inflammatory Target

Dan Peer,1 Eun Jeong Park,1 Yoshiyuki Morishita,1 Christopher V. Carman,2 Motomu Shimaoka1*

Abstract: Cyclin D1 (CyD1) is a pivotal cell cycle–regulatory molecule and a well-studied therapeutic target for cancer. Although CyD1 is also strongly up-regulated at sites of inflammation, its exact roles in this context remain uncharacterized. To address this question, we developed a strategy for selectively silencing CyD1 in leukocytes in vivo. Targeted stabilized nanoparticles (tsNPs) were loaded with CyD1–small interfering RNA (siRNA). Antibodies to β7 integrin (β7 I) were then used to target specific leukocyte subsets involved in gut inflammation. Systemic application of β7 I-tsNPs silenced CyD1 in leukocytes and reversed experimentally induced colitis in mice by suppressing leukocyte proliferation and T helper cell 1 cytokine expression. This study reveals CyD1 to be a potential anti-inflammatory target, and suggests that the application of similar modes of targeting by siRNA may be feasible in other therapeutic settings.

1 Immune Disease Institute and Department of Anesthesia, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
2 Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.

* To whom correspondence should be addressed. E-mail: shimaoka{at}cbrinstitute.org


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