RNA interference strategies as therapy for respiratory viral infections

Abstract

RNA interference (RNAi) is a recently discovered, naturally occurring intracellular process that regulates gene expression through the silencing of specific mRNAs. Methods of harnessing this natural pathway are being developed that allow the catalytic degradation of targeted mRNAs using specifically designed complementary small-interfering RNAs (siRNA). siRNAs are being chemically modified to acquire drug-like properties. Numerous recent high profile publications have provided proofs of concept that RNAi may be of therapeutic use. Much of the design of these siRNAs can be accomplished bioinformatically, thus potentially expediting drug discovery and opening new avenues of therapy for many uncommon, orphan, or emerging diseases. Although endogenous human disease targets can theoretically be affected by RNAi therapeutics, nonendogenous targets (eg, viral targets) are attractive and RNAi therapeutics have been shown to act as antivirals in vivo and in vitro. Respiratory viral infections are particularly attractive targets for RNAi therapeutics because the infected cells exist at the air-lung interface, thereby positioning these cells to be accessible to topical administration of siRNA, for example by aerosol. RNAi therapeutics have been shown to be active against respiratory syncytial virus, parainfluenza and influenza in vitro and in vivo resulting in profound antiviral effects. The first RNAi therapeutic to be designed as an anti-infective medication has now entered proof of concept clinical trials in man. A discussion of the science behind RNAi is followed by a presentation of the potential practical issues in applying this technology to respiratory viral diseases. RNAi may offer new strategies for the treatment of respiratory syncytial virus and other respiratory viruses.