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

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

RNAi technology has been under rapid development for the last decade. The therapeutic potential of RNAi molecules in airway diseases has been demonstrated in several clinical studies (Table 6) , and they could be the solution to some unmet medical needs. No RNAi therapeutics has gained approval by regulatory authority at the time this manuscript was prepared. While delivery is generally considered as the major obstacle to RNAi therapeutics development, it is interesting to notice that siRNAs or miRNA mimics do not need a carrier to generate therapeutic effects following pulmonary delivery. The cellular uptake mechanism of naked RNA in the airways is not clear, but this is certainly an attractive feature that allows simple formulation without the need of delivery vectors. Chemically modified siRNA or miRNA is necessary to improve the stability of the RNA molecules. On the other hand, the delivery of shRNA or miRNA encoding plasmids requires viral vectors to ensure efficient transduction and the subsequent expression of RNAi molecules. However, the use of viral vectors could raise safety concerns for clinical applications, especially when they are used for pulmonary delivery. The employment of liposomal or polymer based nanoparticle delivery technology could be a promising approach. Whether the nanoparticles or naked RNA are used, it is important to evaluate the pharmacokinetic profile of each delivery system to ensure the RNAi therapeutics are localized at the site of action but not quickly distributed to other organs in the body. In terms of formulation of RNAi therapeutics, dry powder aerosol is preferred over the liquid aerosol due to higher stability and the dry powder inhalers are easier to operate with better lung deposition [229] . This would be the direction for RNAi formulation development. Among the different types of RNAi molecules for therapeutic development, siRNA has made significant progress, with a couple of clinical studies investigate the pulmonary delivery of siRNA to treat respiratory diseases. There are also a growing number of clinical pipelines involving the use of siRNA and other RNAi molecules. Several key questions are raised that need to be answered. For infectious diseases, as demonstrated in several in vivo studies, it appears that RNAi is more effective in prophylactic regimen than in therapeutic regimen. How can we improve the therapeutic efficacy of RNAi in combating infections to make it clinically relevant? For inflammatory diseases, long-term therapy is expected. How can we minimize the undesirable effects when cytokines/chemokines are being targeted? When the respiratory functions are compromised in patients with lung disease, is pulmonary delivery a suitable route for administration? As complicated signaling pathway is involved in the pathogenesis of different lung disorders, a thorough investigation of the underlying pathological mechanisms of the disease is a prerequisite for identifying the target of RNAi. Despite the challenges and obstacles, we believe that the pulmonary delivery of RNAi molecules targeting airway diseases is promising.