Abstract

Lethal Respiratory Viral Infections and the Delivery Barrier – Using Stealth siRNAs for Therapy

Nigel McMillan, Associate Professor, Griffith University

RNA interference (RNAi) may provide a therapeutic solution to many pulmonary epithelium diseases. However, the main barrier to the clinical use of RNAi remains the lack of efficient delivery vectors. Research has mainly concentrated on the intranasal route of delivery of short interfering RNA (siRNA) effector molecules for the treatment of respiratory diseases. However, this may be complicated in a diseased state due to the increased fluid production and tissue remodeling. Therefore, we investigated our hydration of a freeze-dried matrix (HFDM) formulated liposomes for systemic delivery to the lung epithelium. We show that 64% of endothelial and 45% of epithelial murine lung cells receive siRNA delivery upon intravenous (IV) administration. Furthermore, we demonstrate that this delivery is functional as it resulted in targeted gene knockdown throughout the lung. This is the first description of lung epithelial delivery via cationic liposomes, and provides a proof of concept for the use of IV liposomal RNAi delivery to specifically knockdown targeted genes in the respiratory system. We will present our latest in vivo data using this approach to treat viral infections including RSV and Hendravirus, a member of the henipaviruses family with a human case fatality rate of over 50%. We will also outline our data using modified siRNAs that have immunostimulatory properties. This approach provides an attractive alternate therapeutic delivery strategy for the treatment of viral infections were intranasal delivery is compromised by post-infection inflammation and poor delivery.