Future Promise of siRNA and Other Nucleic Acid Based Therapeutics for the Treatment of Chronic HCV

Abstract

RNA interference (RNAi) is gaining favor as a potential therapeutic option for the treatment of Hepatitis C virus infections. RNAi, first discovered in plants, induces sequence specific degradation of messenger RNA following the introduction of short interference RNA (siRNA). RNAi is a natural defense mechanism used by plants to combat viral infections, and the discovery of RNAi activity in mammalian cells has prompted several drug companies to investigate and exploit RNAi based drugs as a potential therapy against HCV infections. A number of research groups have demonstrated that strong RNAi activity can be induced against HCV using synthetic siRNA duplexes as triggers, or by expressing short hairpin RNAs from plasmid or viral vectors. However, much work remains to improve delivery, maintain specificity and limit the development of virus resistance. HCV is capable of evading RNAi activity through the incorporation escape mutations within the siRNA target sequence, highlighting the importance of implementing strategies to limit the development of resistance. Other nucleic acid based therapies such as antisense oligonucleotides, RNA aptamers and ribozymes have also been considered for use as HCV therapeutics, and we will outline the potential opportunities and obstacles to their use as well as RNAi.