Gene Therapies for Hepatitis C Virus

Abstract

Hepatitis C virus (HCV) is a leading cause of chronic hepatitis and infects approximately three to four million people per year, about 170 million infected people in total, making it one of the major global health problems. In a minority of cases HCV is cleared spontaneously, but in most of the infected individuals infection progresses to a chronic state associated with high risk to develop liver cirrhosis, hepatocellular cancer, or liver failure. The treatment of HCV infection has evolved over the years. Interferon (IFN)-α in combination with ribavirin has been used for decades as standard therapy. More recently, a new standard-of-care treatment has been approved based on a triple combination with either HCV protease inhibitor telaprevir or boceprevir. In addition, various options for all-oral, IFN-free regimens are currently being evaluated. Despite substantial improvement of sustained virological response rates, some intrinsic limitations of these new direct-acting antivirals, including serious side effects, the risk of resistance development and high cost, urge the development of alternative or additional therapeutic strategies. Gene therapy represents a feasible alternative treatment. Small RNA technology, including RNA interference (RNAi) techniques and antisense approaches, is one of the potentially promising ways to investigate viral and host cell factors that are involved in HCV infection and replication. With this, newly developed gene therapy regimens will be provided to treat HCV. In this chapter, a comprehensive overview guides you through the current developments and applications of RNAi and microRNA-based gene therapy strategies in HCV treatment.

Antisense RNA: the new favorite in genetic research

“…For HCV treatment, antisense RNA can be efficiently employed to inhibit the translation of HCV RNAs in human hepatocellular carcinoma cells via introducing antisense RNAs with the highly conserved 5' region of the HCV genome at genetic loci 1-402 (Wakita et al, 1999). Additional examples of the use of antisense RNAs for inhibiting HCV replication are summarized in the previous review (Verstegen et al, 2015). In addition, antisense RNAs are also widely used in IV treatment, which causes considerable morbidity and mortality in humans and animals (Salomon and Webster, 2009).…”

Generation of Combinatorial Lentiviral Vectors Expressing Multiple Anti-Hepatitis C Virus shRNAs and Their Validation on a Novel HCV Replicon Double Reporter Cell Line

“…Furthermore, several studies have clearly showed that, as in the case of HIV, the simultaneously expression of more than one RNAi sequences is more efficient in blocking viral replication as well as in preventing escape mutations [ 57 , 58 ]. In this context, the simultaneous targeting of viral and host factors involved in viral replication represents a successful strategy in terms of both antiviral effect and prevention of viral mutant selection [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ].…”

“…Thus, RNAi might represent a promising therapeutic tool against HCV as targeting viral genome through specific siRNAs should halt viral replication and propagation. Furthermore, it has been previously demonstrated that not only silencing of viral factors, but also interfering with cellular proteins known to play a role in HCV life cycle, would block viral replication [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. In particular, it has been shown that combinatorial strategies based on the co-expression of arrays of siRNAs targeting multiple viral and/or cellular genes displayed synergistic anti-HCV effects, hence reducing the possibility of resistant variant emergence [ 13 , 14 , 15 , 16 ].…”

Editorial: New Therapies, Markers and Therapeutic Targets in HCV Chronic Infection and HCV Extrahepatic Manifestations

“…Moreover miRNAs induced by HCV can indirectly control critical virus-associated host pathways, inducing liver fibrosis, cirrhosis, and/or hepatocellular carcinoma [38,39]. Treatment for HCV infection has recently progressed from poorly tolerated IFN-α therapy and with very low cure rates, to highly effective oral DAAs with cure rates above 90% for almost all patients, and with little adverse effects [44][45][46] The occurrence of autoimmune thyroiditis, hypothyroidism, papillary thyroid cancer and type 2 diabetes is also more frequent in CHC: these disorders can significantly impact the quality of life of HCV patients, the course of the disease, and the effect of therapies [95][96][97][98]. The role of DAAs in the prevention and treatment of these endocrine disorders remains to be clarified.…”