Journal
MOLECULAR THERAPY
Volume 21, Issue 4, Pages 825-833Publisher
CELL PRESS
DOI: 10.1038/mt.2013.19
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Funding
- Flight Attendant Medical Research Institute YCSA [062572]
- Alpha-1 Foundation Research Grant
- American Lung Association [5R21HL086414-02, 5R01HL079392, UL1-TR000157]
- [1K08HL103771-01]
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Although RNA interference (RNAi) has become a ubiquitous laboratory tool since its discovery 12 years ago, in vivo delivery to selected cell types remains a major technical challenge. Here, we report the use of lentiviral vectors for long-term in vivo delivery of RNAi selectively to resident alveolar macrophages (AMs), key immune effector cells in the lung. We demonstrate the therapeutic potential of this approach by RNAi-based downregulation of p65 (RelA), a component of the pro-inflammatory transcriptional regulator, nuclear factor kappa B (NF-kappa B) and a key participant in lung disease pathogenesis. In vivo RNAi delivery results in decreased induction of NF-kappa B and downstream neutrophilic chemokines in transduced AMs as well as attenuated lung neutrophilia following stimulation with lipopolysaccharide (LPS). Through concurrent delivery of a novel lentiviral reporter vector (lenti-NF-kappa B-luc-GFP) we track in vivo expression of NF-kappa B target genes in real time, a critical step towards extending RNAi-based therapy to longstanding lung diseases. Application of this system reveals that resident AMs persist in the airspaces of mice following the resolution of LPS-induced inflammation, thus allowing these localized cells to be used as effective vehicles for prolonged RNAi delivery in disease settings. Received 2 March 2012; accepted 9 January 2013; advance online publication 00 Month 2013. doi:10.1038/mt.2013.19
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