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

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

In 2005, Bitko et al. reported the inhibition of RSV and parainfluenza virus (PIV) replication by siRNA targeting viral phosphoprotein (P protein), a crucial subunit of the viral RNA-dependent RNA polymerase. Since RSV replicate primarily in the superficial layer of the respiratory epithelium, local delivery of RNAi molecules to the lungs is a rational approach to inhibit RSV replication [139] . In the study, TransIT-TKO was employed as transfection agent and the siRNA was administered to the lungs of BALB/c mice by intranasal instillation 4 h before viral challenge. The RSV and PIV titer was reduced by over 90% five days after infection. The use of naked siRNA also showed substantial inhibition of infection, with approximately 70%-80% efficiency achieved as compared to complexed siRNA. Interestingly, the administration of siRNA before and concomitant with RSV infection was more effective in reducing viral load than treatment after infection [123] . The prophylactic regimen may not be a clinically attractive approach. To achieve optimal therapeutic benefit, fast detection and early intervention are crucial for the prognosis of RSV infection. It is desirable to initiate the antiviral RNAi therapy as quickly as possible once RSV infection is confirmed in clinical practice. P protein may not be an ideal target as it is limited by its specificity to a particular viral strain [124] . Another siRNA, ALN-RSV01, was designed to target the highly conserved region of the mRNA encoding viral nucleocapsid protein (N protein). N protein is a core protein in the RNA polymerase and plays a key role in the replication cycle of RSV [140] . After intranasal administration of ALN-RSV01 to the lungs of mouse at 4 h prior to viral infection, 2.5-to 3.0-log-unit reductions in viral load was observed in comparison with the mismatch siRNA control. For the treatment regimen, comparable antiviral efficacy was achieved in multiple daily doses of ALN-RSV01 at day 1, 2 and 3 post-infection [124] .