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

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

miRNA is a naturally occurring non-coding RNA that plays a key role in regulating gene expression. Primary miRNA (pri-miRNA) is transcribed by RNA polymerase II from endogenous miRNA gene in the nucleus. The hairpin-containing pri-miRNA is structurally similar to the pri-shRNA, therefore the maturation pathway of miRNA is also similar to shRNA [18] . The pri-mRNA is converted by Drosha/DCGR8 complex into precursor miRNA (pre-miRNA), which contains 70-100 nucleotides with interspersed mismatches and adopts a loop structure. The pre-miRNA is subsequently transported to the cytoplasm by Exp5, and is processed by the Dicer into mature miRNA of 18-25 nucleotides in length [21] . As opposed to siRNA, the antisense strand of miRNA is only partially complementary to the target mRNA, leading to gene silencing via translational repression and/or mRNA deadenylation. Position 2 to 7 of the 5 end of the miRNA is the "seed sequence", which is essential for target recognition, and the miRNA binding sites of mRNA are located in the 3 untranslated region (UTR) [22] . There are two major approaches of miRNA-based therapeutics: (i) miRNA inhibition [23, 24] , which suppresses the action of the endogenous miRNA by antisense oligonucleotide (antimiR); and (ii) miRNA replacement [25, 26] , which introduces synthetic miRNA (miRNA mimic) to restore the functions of the endogenous miRNA. Only the latter is discussed in this review. Compared to siRNA-based therapeutics, miRNA has the potential to target multiple genes due to the imperfect binding to the target mRNA [27] .