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

Abstract

RNA interference (RNAi) is a potent and specific post-transcriptional gene silencing process. Since its discovery, tremendous efforts have been made to translate RNAi technology into therapeutic applications for the treatment of different human diseases including respiratory diseases, by manipulating the expression of disease-associated gene(s). Similar to other nucleic acid-based therapeutics, the major hurdle of RNAi therapy is delivery. Pulmonary delivery is a promising approach of delivering RNAi therapeutics directly to the airways for treating local conditions and minimizing systemic side effects. It is a non-invasive route of administration that is generally well accepted by patients. However, pulmonary drug delivery is a challenge as the lungs pose a series of anatomical, physiological and immunological barriers to drug delivery. Understanding these barriers is essential for the development an effective RNA delivery system. In this review, the different barriers to pulmonary drug delivery are introduced. The potential of RNAi molecules as new class of therapeutics, and the latest preclinical and clinical studies of using RNAi therapeutics in different respiratory conditions are discussed in details. We hope this review can provide some useful insights for moving inhaled RNAi therapeutics from bench to bedside.

Keywords: RNA interference; inhalation; microRNA (miRNA); pulmonary delivery; respiratory diseases; short hairpin RNA (shRNA); short interfering RNA (siRNA).

Figure 1

Mechanism of RNA interference (RNAi) induced gene silencing. Short interfering RNA (siRNA) can be produced inside the cells from double stranded RNA (dsRNA) or expressed from short hairpin RNA (shRNA) vector, or chemically synthesized in the laboratory. Its gene silencing effect is dependent upon fully complementary binding of the target messenger RNA (mRNA). MicroRNA (miRNA) is a naturally occurring molecule. It can also be expressed from miRNA vector or chemically synthesized (miRNA mimic). miRNA mediates gene silencing via the partial complementary binding of the target mRNAs.

Figure 2

Summary of the major barriers associated with pulmonary delivery of RNAi molecules.

Figure 3

The three major mechanisms of particles deposition in the lungs. Inertia impaction occurs when large particles (>5 µm) cannot adjust to the change of airflow direction due to inertia and deposit on the airway walls, typically in the upper respiratory tract. Gravitational sedimentation is the settling of particles due to gravitational force. It mainly affects particles with size of 1–5 µm, which usually deposit in the small airways. Diffusion occurs when submicron-size particles having Brownian motion hit the surface of airway walls.