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

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

Another strategy is to modulate host immune response to improve the antimicrobial ability of the host [49] . One of the key characteristics of TB infection is the formation of granuloma, which is a compact, organized aggregate of immune cells. Granuloma is previously considered as a host-protective structure to sequester the infecting mycobacteria, but recent work revealed that the pathogens could take advantage of granuloma formation to facilitate their proliferation and dissemination in the host [157] , as it provides a hospitable environment for mycobacteria to survive and replicate over a long period of time. There is a complicated chemokines and cytokines network involved in the granulomatous response. RNAi can be used to target immunosuppressive cytokines in order to inhibit the growth of Mtb. Among them, tumor necrosis factor (TNF)-α and IFN-γ are critical in activating macrophages and triggering the formation of granuloma [158] . XCL1 (lymphotactin) is a chemokine produced by activated CD8 + T cells during chronic TB infection. It was suggested that XCL1 regulates IFN-γ production by CD4 + T cells and contribute to the stability of the granuloma [159] . When a single dose of siRNA targeting XCL1 was delivered to the lungs of mice that were chronically infected with TB, the expression of XCL1 was effectively inhibited. The suppression of XCL1 expression in the lungs was associated with the decreasing number of T lymphocytes, reduction in the IFN-γ response, disorganized granulomatous lesions and higher fibrosis [130] . Although the inhibition effect elicited by siRNA was transient and did not provide significant therapeutic benefit, this proof-of-concept study demonstrated that the local-environment and immunopathology of the lungs can be modulated to favor host response via pulmonary delivery of siRNA.