Anti-HCV therapies in chimericscid-Alb/uPA mice parallel outcomes in human clinical application

Kneteman, Norman M.; Weiner, Amy J.; O’Connell, John F.; Collett, Marc S.; Gao, Tiejun; Aukerman, Lea; Kovelsky, Rosemary; Ni, Zhi; Hashash, Ahmad; Kline, Janine; Hsi, Belinda; Schiller, Dan; Douglas, Donna N.; Tyrrell, D. Lorne; Mercer, David F.

doi:10.1002/hep.21209

Cited by 95 publications

(79 citation statements)

References 19 publications

(19 reference statements)

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“…A saturated reduction of approximately 2 log 10 -fold after treatments with BILN 2061 and IFN was also reported in an analogous mouse model (Kneteman et al, 2006;Vanwolleghem et al, 2007). These observations led us to examine HCV replication in the chimeric human liver.…”

Section: Discussionsupporting

confidence: 57%

“…Several groups have developed a small-animal model for HCV infection using homozygous urokinase-type plasminogen activator (uPA)/severe combined immunodeficiency (SCID) (uPA +/+ /SCID +/+ ) mice transplanted with human hepatocytes (Mercer et al, 2001). These mice are susceptible to cell culture-grown HCV (HCVcc; Lindenbach et al, 2006) and have been used to evaluate antiviral agents including IFN-a, BILN 2061 (an NS3-4A protease inhibitor) and HCV796 (an NS5B polymerase inhibitor) (Kneteman et al, 2006(Kneteman et al, , 2009Vanwolleghem et al, 2007). However, the HCV clearance rate in the SCID mouse model and the virion production rate in hepatocytes engrafted in the mouse liver are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

“…After the infection with HCV genotype 1b, high viral loads were maintained in the mice for more than 6 months. Recent studies have indicated the utility of a human/mouse chimera model for HCV infection to evaluate antiviral efficacy (Kneteman et al, 2006(Kneteman et al, , 2009) and preclinical safety (Vanwolleghem et al, 2007). However, PK/PD studies and estimations of virus clearance rate have rarely been performed in this mouse model.…”

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confidence: 99%

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Practical evaluation of a mouse with chimeric human liver model for hepatitis C virus infection using an NS3-4A protease inhibitor

Kamiya¹,

Iwao²,

Hiraga

et al. 2010

Journal of General Virology

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A small-animal model for hepatitis C virus (HCV) infection was developed using severe combined immunodeficiency (SCID) mice encoding homozygous urokinase-type plasminogen activator (uPA) transplanted with human hepatocytes. Currently, limited information is available concerning the HCV clearance rate in the SCID mouse model and the virion production rate in engrafted hepatocytes. In this study, several cohorts of uPA +/+ /SCID +/+ mice with nearly half of their livers repopulated by human hepatocytes were infected with HCV genotype 1b and used to evaluate HCV dynamics by pharmacokinetic and pharmacodynamic analyses of a specific NS3-4A protease inhibitor (telaprevir). A dose-dependent reduction in serum HCV RNA was observed. At telaprevir exposure equivalent to that in clinical studies, rapid turnover of serum HCV was also observed in this mouse model and the estimated slopes of virus decline were 0.11-0.17 log 10 h "1 . During the initial phase of treatment, the log 10 reduction level of HCV RNA was dependent on the drug concentration, which was about fourfold higher in the liver than in plasma. HCV RNA levels in the liver relative to human endogenous gene expression were correlated with serum HCV RNA levels at the end of treatment for up to 10 days. A mathematical model analysis of viral kinetics suggested that 1 g of the chimeric human liver could produce at least 10 8 virions per day, and this may be comparable to HCV production in the human liver. INTRODUCTIONHepatitis C virus (HCV) is a major cause for concern worldwide. More than 3 % of the world's population is chronically infected with HCV and 3-4 million people are newly infected each year (Wasley & Alter, 2000). Chronic HCV infection is relatively mild and progresses slowly; however, about 20 % of chronic hepatitis C (CHC) carriers progress to serious end-stage liver disease (Lauer & Walker, 2001;Liang et al., 2000;Poynard et al., 2003). The current standard treatment for HCV infection is administration of pegylated alpha interferon (PEG-IFN) in combination with ribavirin (RBV) for 48 weeks. The overall cure rates with this intervention are 40-50 % for patients with genotype 1 and more than 75 % for patients with genotypes 2 and 3 (Fried et al., 2002;Manns et al., 2001). Several compounds that inhibit specific stages of the virus life cycle have been clinically evaluated (Manns et al., 2007;Pereira & Jacobson, 2009). Telaprevir is a novel peptidomimetic slow-and tight-binding inhibitor of HCV NS3-4A protease, which was discovered using a structure-based drug design approach (Perni et al., 2006). A rapid decline in viral RNA was observed in CHC patients treated with telaprevir (Reesink et al., 2006) and an increased antiviral effect of a combination of telaprevir and PEG-IFN has been reported (Forestier et al., 2007). Recent clinical trials of telaprevir in combination with PEG-IFN and RBV have indicated a promising material advance in therapy for CHC patients (Hézode et al., 2009;McHutchison et al., 2009). Firstgeneration HCV-specific agents have been...

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Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Practical evaluation of a mouse with chimeric human liver model for hepatitis C virus infection using an NS3-4A protease inhibitor

Kamiya¹,

Iwao²,

Hiraga

et al. 2010

Journal of General Virology

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“…A genotype-dependent antiviral IFN effect in chimeric mice has been observed by several groups. 75,76 Moreover, in infected chimeric uPA/SCID mice treated with the HCV NS3 protease inhibitor BILN-2061, clinical and ultrastructural signs of cardiotoxicity appeared. 77 This further demonstrates the validity of the model, because cardiotoxicity was also observed in rhesus monkeys treated with BILN-2061, which led to the cessation of further clinical development of this compound.…”

Section: Small-animal Models For Hcv Infectionmentioning

confidence: 99%

Experimental models for hepatitis C viral infection

Boonstra¹,

Laan²,

Vanwolleghem³

et al. 2009

Hepatology

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Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The majority of infected individuals develop a persistent infection, which is associated with a high risk of liver cirrhosis and hepatocellular carcinoma. Since its discovery 20 years ago, progress in our understanding of this virus has been suboptimal due to the lack of good model systems. However, in the past decade this has greatly accelerated with the development of various in vitro cell culture systems and in vivo small-animal models. These systems have made a major impact on the field of HCV research, and have provided important breakthroughs in our understanding of HCV infection and replication. Importantly, the in vitro cell culture systems and the small-animal models have allowed preclinical testing of numerous novel antiviral compounds for the treatment of chronic HCV infection. In this article, we give an overview of current models, discuss their limitations, and provide future perspectives for research directed at the prevention and cure of hepatitis C. (HEPATOLOGY 2009;50:1646-1655.) Hepatitis C Virus Pathology and BiologyThe hepatitis C virus (HCV) is considered a successful pathogen in establishing persistent infections by evading the immune system. Only a fraction of acutely infected individuals are able to clear the infection spontaneously, whereas about 80% of the infected individuals develop a chronic infection. 1,2 The symptoms are initially mild in these persistently infected patients, and it may take decades before the serious consequences of chronic HCV infection become apparent. Patients with chronic HCV are at increased risk for developing liver fibrosis, cirrhosis, and/or hepatocellular carcinoma. Currently, these longterm complications of chronic HCV infection are the leading indication for liver transplantation. 3,4 Because of the high incidence of new infections by blood transfusions in the 1980s before discovery of the virus, and because morbidity associated with chronic HCV infections generally takes decades to develop, it is expected that the burden of disease in the near future will rise dramatically.HCV is an enveloped flavivirus, with a positivestranded RNA genome of approximately 9600 nucleotides and is composed of a single open reading frame, which encodes a polyprotein precursor of approximately 3000 amino acids. The coding region is flanked by 5Ј and 3Ј noncoding regions, which are important for the regulation of genomic duplication as well as initiation of translation. The single polyprotein is cleaved by host and viral proteases into individual structural and nonstructural (NS) proteins (Fig. 1A). Replication of the HCV genome involves the synthesis of a full-length negative-stranded RNA intermediate, which in turn provides a template for the de novo production of positive-stranded RNA. Both these synthesis steps are mediated by the viral RNA-dependent RNA polymerase NS5B. 5-7 NS5B lacks proofreading abilities, and this leads to a high mutation rate and the generation of numerous quasispecies. ...

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“…Après des croisements successifs avec des animaux de fond génétique immunodéprimé SCID, les souris uPA permirent l'implantation, le maintien et la prolifération d'hépatocytes humains [3]. Il ne restait alors plus qu'à démontrer que ces souris au foie partiellement humanisé étaient infectables par le VHC et, ainsi, à confirmer l'efficacité thérapeutique de différentes drogues comme l'interféron ou les antiprotéases [4]. L'importance de la réponse immunitaire innée dans l'histoire naturelle de l'infection virale C a également pu être démontrée grâce à ce modèle [5].…”

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Des souris humanisées pour l’étude du virus de l’hépatite C

Gilgenkrantz

2011

Med Sci (Paris)

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Anti-HCV therapies in chimericscid-Alb/uPA mice parallel outcomes in human clinical application

Cited by 95 publications

References 19 publications

Practical evaluation of a mouse with chimeric human liver model for hepatitis C virus infection using an NS3-4A protease inhibitor

Practical evaluation of a mouse with chimeric human liver model for hepatitis C virus infection using an NS3-4A protease inhibitor

Experimental models for hepatitis C viral infection

Des souris humanisées pour l’étude du virus de l’hépatite C

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