RNA Interference: A Promising Approach for the Treatment of Viral Hepatitis

Abstract

Hepatitis viruses are the leading cause of liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. The hepatitis C virus (HCV), together with the hepatitis B virus (HBV), accounts for 75% of all cases of liver disease around the world, with chronic hepatitis, cirrhosis, and HCC causing 500,000 to 1.2 million deaths per year [1][2][3]. More than 170 million people worldwide have chronic HCV infection. According to the 2002 WHO report, chronic liver diseases were responsible for 1.4 million deaths, including 796,000 deaths due to cirrhosis and 616,000 deaths due to primary liver cancer. At least 20% of these deaths (more than 280,000 deaths) are probably attributable to HCV infection [4]. With the WHO officially recognizing hepatitis as a global health issue, more research needs to be conducted to develop new therapeutic interventions. Current antiviral therapies for chronic viral hepatitis are effective only in approximately half of the patients [5]. The most widely available agents for the treatment of chronic hepatitis are interferon-α (IFN-α) and nucleoside analogs such as lamivudine or adefovir [6][7]. However, treatment with these agents has some disadvantages, including possible serious adverse effects in the case of interferon treatment or recurrence of viremia after discontinuation of therapy and development of resistant mutants after prolonged lamivudine treatment [8][9][10][11]. Moreover, nucleoside analogs such as 3TC-lamivudine only interfere with viral replication and do not induce cessation of the process. The low efficacy of these agents, their adverse effects, and development of resistant viral mutations are major impediments to the clinical application of these agents for the treatment of viral hepatitis [6]. These shortcomings necessitate the development of alternative treatment strategies. Sequence-specific gene silencing using RNA interference (RNAi) is a Nobel prize-winning technology that represents a promising new approach to overcome viral infections [5][12][13][14]. RNA interference is an evolutionary mechanism for protecting the genome against invasion by mobile genetic elements such as transposons and viruses [6]. It is a process by which small interfering RNA (siRNA) with specific target sequences induce silencing of homologous genes by binding to their complementary mRNA and inducing the elimination of the mRNA molecule [15]. This process occurs post-transcriptionally in the cytoplasm and is mediated by small RNA molecules (21 to 25 nucleotides in length) that bind to their complementary mRNA targets and silence the expression of these targets [6]. The phenomenon of RNA interference (RNAi) was first described by Fire et al. They observed that in the nematode Caenorhabditis elegans, the presence of double-stranded RNA (dsRNA) resulted in sequence-specific gene silencing at the post-transcriptional level. The RNAi pathway has since been recognized as a conserved biological pathway, and several experimental models have contributed to the understanding of this process [15][16].