Journal
JOURNAL OF CONTROLLED RELEASE
Volume 313, Issue -, Pages 33-41Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2019.10.001
Keywords
IBD; Nanoparticle; LNP; IRF8; Immunomodulation; RNAi
Funding
- Marian Gertner Institute of Medical Nanosystems
- Dan David Fellowship Award
- Bruce and Ruth Rappaport Foundation
- Iafa Keidar Prize
- Dotan Center for Hemato-Oncology at Tel Aviv University
- ERC grant LeukoTheranostics [647410]
- European Research Council (ERC) [647410] Funding Source: European Research Council (ERC)
Ask authors/readers for more resources
Interferon regulatory factor 8 (IRF8) protein plays a critical role in the differentiation, polarization, and activation of mononuclear phagocytic cells. In light of previous studies, we explored the therapeutic potential of IRF8 inhibition as immunomodulatory therapy for inflammatory bowel disease (IBD). To this end, we utilized siRNA-loaded lipid-based nanoparticles (siLNPs) and demonstrated a similar to 90% reduction of IRF8 mRNA levels in vitro (PV < 0.0001), alongside a notable reduction in IRF8 protein. Moreover, silencing IRF8 ex vivo in splenocytes lead to a profound downregulation of IRF8 protein, followed by an immunomodulatory effect, as represented by a decrease in the secretion of TNF alpha, IL6 and IL12/IL23 (IL12p40) proinflammatory cytokines (PV = 0.0045, 0.0330, <0.0001, respectively). In order to silence IRF8 in vivo, selectively in inflammatory leukocytes, we used siLNPs that were coated with anti-Ly6C antibodies via our recently published ASSET targeting approach. Through this strategy, we have demonstrated a selective binding of the targeted-LNPs (T-LNPs) to Ly6C + inflammatory leukocytes. Finally, an immunomodulatory effect was demonstrated in vivo in an IBD mouse model with a profound decrease of TNF alpha, IL6, IL12/IL23, and IL1 beta pro-inflammatory cytokines (n = 5, PV < 0.0001, <0.0001, <0.0001, 0.02, respectively) and an improvement of colon-morphology as assessed by colon-length measurements and colonoscopy (PV < 0.0001). Overall, using antibody-targeted siLNPs, we showed a notable reduction of IRF8 mRNA and protein and demonstrated a targeted immunomodulation therapeutic effect ex vivo and in vivo, in the DSS colitis model. We claim that a selective silencing of IRF8 in inflammatory leukocytes (such as Ly6C+) may serve as a therapeutic approach for treating inflammatory disorders.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available