All for One, One for All: New Combinatorial RNAi Therapies Combat Hepatitis C Virus Evolution

Abstract

Roughly two decades after its discovery and cloning, hepatitis C virus (HCV)—a pathogen infecting up to 180 million people worldwide and capable of causing severe liver disease, including cirrhosis and hepatocellular carcinoma—remains a frustrating target for development of antiviral therapies. Two articles in this issue of Molecular Therapy now report combinatorial RNA interference (coRNAi) strategies1 against multiple HCV genotypes that aim to balance in vivo safety, efficiency, and specificity, and that promise to restrict viral escape mutants. In the first study, Chandra et al.2 used lipid nanoparticles called nanosomes to encapsulate two preselected potent anti-HCV small interfering RNAs (siRNAs), and show that six daily combined systemic injections sufficed to significantly block HCV replication in a liver xenograft mouse model. In the second report, Suhy et al.3 optimized an adeno-associated viral (AAV) vector of serotype 8 for robust and safe expression of three short hairpin RNAs (shRNAs) targeting conserved regions of the HCV genome, and demonstrate its sustained performance in the livers of nonhuman primates (NHPs) following a single intravenous injection. By validating the concept of nonviral- or viral vector–mediated coRNAi against rapidly evolving targets in different animal models, the studies represent an important step forward in our efforts to translate newer vector and RNAi designs into clinical therapies for HCV.