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Hepatitis C Virus
HCV is an RNA virus that causes chronic hepatitis that afflicts an estimated 200 million individuals worldwide. The virus is transmitted by the transfer of body fluids (primarily blood) from infected individuals. Those who abuse intravenous drugs, those who received blood transfusions prior to 1992, and health-care workers, account for the majority of infected patients. The level of morbidity and mortality associated with HCV is high. The majority of infected patients remain infected for life and a significant percentage of HCV-infected patients ultimately progress to cirrhosis, liver failure, or hepatocellular carcinoma (liver cancer). HCV infection has become the major reason for liver transplantation in the U.S. An estimated 3.9 million Americans are chronically infected with Hepatitis C. This is four times the number of those estimated to be infected with the human immunodeficiency virus (HIV). One out of every 50 Americans is infected with HCV and 75% of those individuals do not realize they are infected. The Centers for Disease Control and Prevention (CDC) estimates the U.S averages 18,000 new infections annually in addition to approximately 12,000 deaths caused by HCV.
Unlike hepatitis A and B, no vaccine exists to prevent HCV infection. The best available treatment is a combination of two broad-spectrum antiviral agents, interferon and ribavirin, with one of two available direct-acting antivirals targeting the HCV serine protease. This therapy does not provide broad cross-genotype coverage and is associated with serious side effects. The hepatitis C virus drug market is experiencing a dramatic growth and
is expected to exceed $15 Billion USD in 2020. This robust growth will be driven primarily by the launch of novel premium priced therapeutics that will increase the cure rate, minimize side effects and drive treatment of an increasing fraction of those infected.
Similar to HIV, HCV has a high predeliction to develop resistance to antiviral drugs. It is expected, therefore, that multi-drug “cocktail” therapies, used in different combinations will be necessary to effectively manage chronic HCV infection. This suggests that the HCV market will be served by numerous therapeutic agents.
Apath can assist clients in developing innovative HCV therapeutics by providing them with access to state-of-the-art anti-HCV development platforms, technological know-how and extensive HCV research experience.
3'NTR
Infectious Clone Technology - Replicons
The 3' non-translated region (3'NTR) is the most conserved region of the hepatitis C virus (HCV) genome (Kolykhalov et al. 1996. J. Virology 70: 3363-71 & Blight et al. 1997. J. Virology 71:7345-52). It is likely to be a critical regulatory region and it has been shown to be required for replication of an infectious clone of HCV in chimpanzees (Kolykhalov et al.1997, Science 277:570-74). The 3' NTR is, therefore, an excellent genomic (RNA) target for an anti-HCV therapy. U.S. 5,874,565 (and related EP 0856051) was assigned to Washington University and licensed exclusively to Apath.
Identification of well-defined and robust cell-culture systems for HCV is critical for identification and evaluation of antivirals against HCV. In 1999, Lohmann et al. described a subgenomic HCV replicon constructed from genotype 1b RNA, and isolated a Huh-7 cell line which contains this autonomously replicating replicon (Lohmann et al. 1999. Science 285:110-13). The replicon system was further enhanced by the discovery of adaptive mutations which allowed more robust replication of the viral RNA in cell culture (Blight et al. 2000. Science 290:1972-74). Replicon technology was expanded to include genotype 1a RNA and respective adaptive mutations (Blight et al. 2003. J. Virology 77:3181-90) as well as genotype 2a RNA (Kato et al. 2003. Gastroenterology 125: 1808-17). Highly Permissive Cell Line Technology While studying replicon cells, it was discovered that replication efficiency was impacted by the state of the host cells. Researchers attempted to identify host cells that had adapted to viral replication to improve efficacy of the cell culture systems. Huh-7.5 cells are a human hepatocyte cell line generated by curing a stably selected HCV replicon-containing Huh-7 cell line with IFN (Blight et al. 2002. J Virology 76: 13001-14). Taking that strategy one step further, researchers at the Scripps Institute cured a stably selected HCV replicon-containing Huh-7.5 cell line with IFN, which resulted in the human hepatocyte cell line Huh-7.5.1 cells (Zhong et al. 2005. PNAS 102:9294-99). HCV Full Virus Life Cycle Technology - HCVcc The first full length viral RNA that was capable of replicating in cell culture and producing infectious virus particles was the JFH-1 sequence. This HCV genotype 2a RNA was developed in the laboratory of Dr. Takaji Wakita at Tokyo Metropolitan Institute of Neuroscience (Wakita et al. 2005. Nat Med. 11: 791-96). In efforts to improve viral titers, chimeric genomes were constructed with sequences of a second genotype 2a sequence, J6. This nucleic acid sequence was shown to be infectious in chimpanzees (Yanagi et al. 1999. Virology 262: 250-63) and was discovered by the group of Dr. Robert H. Purcell at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. J6/JFH was one successful chimeric 2a genome that replicates and produces virus particles that are infectious in cell culture. J6/JFH was developed in the laboratory of Dr. Charles M. Rice at The Rockefeller University (Lindenbach et al. 2005. Science 309:623-26). Another full-length 2a chimera with a different intragenotypic breakpoint, Jc1, was developed in the laboratory of Dr. Ralf Bartenschlager at The University of Heidelberg (Pietschmann et al. 2006. PNAS 103: 7408-13). To expand HCV infectious culture systems to other HCV genotypes, chimeric genomes were constructed. Core-NS2 recombinants are JFH1-based recombinant genomes containing Core, envelope protein 1 and 2 (E1, E2), p7, and nonstructural protein 2 (NS2) from other HCV genotypes. Apath has developed these chimeras using Core-NS2 of genotypes 1a or 1b. An expanded panel of JFH1-based intergenotypic chimeras containing Core-NS2 of genotypes 1 to 7 was developed in the laboratory of Dr. Jens Bukh at Copenhagen University Hospital (Gottwein et al. 2009. Hepatology 49: 364-77 & Gottwein et al. 2011. J. Virology 85: 8913-28). NS5A chimeras were also developed in the laboratory of Dr. Jens Bukh. These JFH1-based recombinant infectious cell culture systems express NS5A of genotypes 1 to 7 (Scheel et al. 2011. Gastroenterology 140: 1032-42). HCV Research and Development Tools Our goal is to assist clients in developing innovative and successful anti-HCV development programs by providing them access to our exceptional research and development tools. Below are links to five papers describing some of our most requested research tools by our global licensees. |