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

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

Increase microvascular permeability is a major cause of amplification of the inflammatory responses in ALI, leading to the progression to severe pathological condition [214] . The integrity of pulmonary and systemic endothelial barrier is maintained by the bioactive lipid, sphingosine-1phosphate (S1P), which can be irreversibly degraded by an enzyme called sphingosine-1-phosphate lyase (S1PLyase) [214] . Therefore, suppressing endothelial S1PLyase expression by siRNA is a potential therapeutic approach to maintain the integrity of the endothelial barrier [217] . Nanoparticles containing siRNA targeting S1PLyase and recombinant high mobility group box-1 A peptide (HMGB1A) were delivered to the lungs of LPS-induced ALI mouse model by intratracheal instillation. HMGB1A peptide is an antagonist of the pro-inflammatory cytokine HMGB1 and provides additional anti-inflammatory effect in ALI. An arginine-rich R3V6 peptide was used as a carrier. S1PLyase level was significantly inhibited in the BALF, leading to a significantly reduction of inflammatory cytokine (TNF-α and IL-6) and inflammatory response in the lungs of the treated animal [11] .