An Example of Hepatitis C Virus
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A Case for Translational Research in Hepatology: An Example of Hepatitis C Virus W. Ray Kim Professor and Chief, Division of Gastroenterology and Hepatology, Stanford University School of Medicine Translational research is commonly defined as applying knowledge learned from basic science to enhance human health and well‐being. The most common type of translational research is to convert basic science to clinical in- formation used for the care of patient (‘bench‐to‐bedside’). However, there is a wider range to the biomedical transla- tional research spectrum as shown below. For translational research in hepatology, there are few better examples than the recent achievements in hepatitis C virus (HCV) and related liver disease research. In a relatively short span of less than 25 years, the research community progressed from the initial discovery and characterization to development of model systems to curative therapeutic agents. Transla onal Research • Biomedical Research Spectrum Basic Clinical Implications Implications Improved Scientific Insights for Practice for Global Discovery Population Health Health T1 T2 T3 T4 In vitro Phase 2 studies Phase 4 Population-level Animal Phase 3 Studies HSR outcomes studies Human - Implementation physiology - Dissemination Social Phase 1 - Communication determinants of Clinical health Outcomes Research www.kasl.org 3 제4회 임상연구방법론 워크숍 Hepatitis C virus (HCV), discovered in 1989, belongs in the Flaviviridae family. Although the initial discovery of immunologic markers of infection and subsequent sequencing of the viral genome quickly led to serologic‐ and nu- cleic acid‐based diagnostics, progress in investigation of the viral lifecycle was hampered by lack of laboratory tools. The only animal which HCV can naturally infect is the chimpanzee ‐ until the development of human‐liver chimeric model in 2001 and genetically modified HCV‐permissive mice in 2011, there were no suitable small animal models. Establishment of cell culture systems also proved difficult – over time, replicon systems, retrovirus‐based pseudo par- ticles and eventually complete viral replication systems were developed. The HCV genome contains 5’‐ and 3’‐untranslated regions (UTRs) flanking one open reading frame (ORF) that is translated via an internal ribosome entry site (IRES). The resulting polyprotein is processed to yield structural (core, E1 and E2) and non‐structural (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins. The structure of the poly- peptide and function of each protein product is shown in the table below. Category Protein Function Structural C Capsid E1 Envelope glycoproteins E2 Non‐structural p7 Viroporin NS2 Autoprotease NS3 Protease/Helicase NS4A NS3 co‐factor NS4B Organizer of replication complex and membranous web NS5A Regulator of replication and viral assembly NS5B RNA‐dependent RNA polymerase Key steps in the life cycle of HCV include entry into the host cell, uncoating of the viral genome, translation of viral proteins, viral genome replication, and the assembly and release of virions. Consequently, there are several potential targets for intervention including (1) the viral particle itself (e.g, neutralizing antibodies, virocidal peptides); (2) entry and receptor interaction (e.g., antibodies and small molecules targeting receptors, kinase inhibitors); (3) translation and polyprotein processing (e.g., NS3‐NS4A protease inhibitors); (4) HCV RNA replication (e.g., NS5B polymerase and NS5A inhibitors, miR‐122 antagonists, cyclophilin inhibitors, statins); (5) assembly and virion morphogenesis (NS5A inhibitors, glycosidase inhibitors, MTP inhibitors). Despite these multiple potential targets for therapy, for over 20 years, therapeutic options at bedside were limited to pre‐existing compounds such as interferon alpha and ribavirin. numerous permutations of that particular combina- tion including increased dosing, lengthening treatment duration and chemically stabilizing the interferon led to grad- ual improvement in response rates from less than 10% to approximately 50% by 2002, albeit at the expense of sig- nificant toxicity, such as fatigue, depression and anemia. 4 대한간학회 W. Ray Kim | A Case for Translational Research in Hepatology: An Example of Hepatitis C Virus Introduction of the first direct acting antiviral (DAA) class in 2011 marked an important break through which led to improvement in response rates up to approximately 70%. The most groundbreaking advance in HCV treatment to date is sofosbuvir, a NS5B polymerase inhibitor, which is expected to constitute a backbone of future combination therapy. Currently available sofosbuvir‐containing regimens lead to response rates of around 95%. Furthermore, there are other compounds under development with response rates close to 100% even in patients who may not re- spond as well as others. It is anticipated that nearly universal cure is possible in the near future for all patients with HCV infection with short term all oral therapy with little toxicity. www.kasl.org 5.