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

2008; American Association for the Advancement of Science; Volume: 319; Issue: 5863 Linguagem: Inglês

10.1126/science.1149859

1095-9203

Dan Peer, Eun Jeong Park, Yoshiyuki Morishita, Christopher V. Carman, Motomu Shimaoka,

Immunotherapy and Immune Responses

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 β 7 integrin (β 7 I) were then used to target specific leukocyte subsets involved in gut inflammation. Systemic application of β 7 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.