Delivery of RNAi Therapeutics to the Airways—From Bench to Bedside

Qiu, Yingshan; Lam, Jenny K. W.; Leung, Susan W. S.; Liang, Wanling

Other targets of RNAi-based immunotherapy include the transforming growth factor β (TGF-β) and interleukin 10 (IL-10) [13] . Both of them are found to be elevated in TB patients, and their high level of expression is connected with TB reactivation [160] . During chronic infection, these cytokines restrain inflammation through affecting helper T cell 1 (T h 1) response and macrophage activation, leading to substantial reduction of their antimicrobial activity [161] . In that study, siRNA targeting TGF-β1 was administered through the intrapulmonary route to IL-10 knockout mice at 60 days post-infection. TGF-β1 gene silencing resulted in the increased expression of the antimicrobial mediators nitric oxide (NO) and inducible nitric oxide synthase (iNOS), and significantly reduced the bacterial load for at least four weeks after treatment. A synergistic effect at improving the antimicrobial activity in the lungs was observed when both IL-10 and TGF-β1 were targeted simultaneously. Although the inhibition of bacterial load in this study was modest, it showed that siRNA immunotherapy is a feasible approach to enhance the host antimicrobial capacity. Moreover, MDR and XDR TB pose huge challenges for the current chemotherapeutic agents. Combined immunotherapy targeting immunosuppressive cytokines and chemotherapy to target drug resistance bacteria population is a direction that is worth future investigation.