Development of Humanized Mice for the Study of Hepatitis C Virus Infection

Turrini, Paolo; Sasso, Renato Nelson; Germoni, S.; Marcucci, Isabella; Celluci, A.; Marco, A. Di; Marra, Emanuele; Paonessa, Giacomo; Eutropi, A.; Laufer, Ralph; Migliaccio, Giovanni; Padrón, Julio Rodríguez

doi:10.1016/j.transproceed.2006.02.149

Cited by 29 publications

(25 citation statements)

References 14 publications

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“…Many recent publications have unambiguously demonstrated the value of humanized mouse livers for the study of drug metabolism and hepatitis research [7][8][9]21,[23][24][25][26][27][28][29] . However, the albumin-uPA transgenic mouse used for these studies has several major practical limitations.…”

Section: Discussionmentioning

confidence: 99%

“…In all of these reports, the animals used were immunodeficient transgenics that express uroplasminogen activator (uPA) under the transcriptional control of an albumin promoter, rendering it hepatotoxic [5][6][7][8][9] . Although engraftment levels of up to 70% have been reported in these models, the system has several major disadvantages that have prevented its widespread use.…”

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confidence: 99%

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Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice

et al. 2007

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Mice that could be highly repopulated with human hepatocytes would have many potential uses in drug development and research applications. The best available model of liver humanization, the uroplasminogen-activator transgenic model, has major practical limitations. To provide a broadly useful hepatic xenorepopulation system, we generated severely immunodeficient, fumarylacetoacetate hydrolase (Fah)-deficient mice. After pretreatment with a urokinaseexpressing adenovirus, these animals could be highly engrafted (up to 90%) with human hepatocytes from multiple sources, including liver biopsies. Furthermore, human cells could be serially transplanted from primary donors and repopulate the liver for at least four sequential rounds. The expanded cells displayed typical human drug metabolism. This system provides a robust platform to produce high-quality human hepatocytes for tissue culture. It may also be useful for testing the toxicity of drug metabolites and for evaluating pathogens dependent on human liver cells for replication.The liver is the principal site for the metabolism of xenobiotic compounds, including medical drugs. Because many hepatic enzymes are species specific, it is necessary to evaluate the metabolism of candidate pharmaceuticals using cultured primary human hepatocytes 1,2 . Today, hepatocytes are isolated primarily from cadaveric organs and then shipped to the location where testing will be performed. The condition (viability and state of differentiation) of hepatocytes from cadaveric sources is highly variable, and many cell preparations are of marginal quality. The availability of high-quality human hepatocytes is further hampered by the fact that they cannot be substantially expanded in tissue culture 3,4 . Hepatocytes from readily available mammalian species, such as the mouse, are not suitable for drug testing because they have a different complement of metabolic enzymes and

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice

et al. 2007

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“…Herpes simplex thymidine kinase, under control of the phosphoglycerate kinase promoter (PGK-tk), has been used to select against random insertion events [36]. The confirmed clones were injected into the blastocysts of C57BL/6 mice then heterozygotes were inter-crossed to obtain lhx2-/-mice.…”

Section: Liver Cancer Mouse Modelmentioning

confidence: 99%

Development of murine models to study Hepatitis C virus induced liver pathogenesis

et al. 2013

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Hepatitis C virus (HCV) is involved in different liver pathologies worldwide. In contemporary scenario, HCV treatment is lagging behind owing to absence of vaccines against virus. The only consideration for HCV treatment is pegylated interferon-alpha and ribavirin that results in sustained virological response in 50 % of patients. Two feasible hosts for HCV infection are chimpanzee and humans. For decades, chimpanzees are sole host to study HCV pathogenesis, but their use is limited due to ethical issues. The dilemma behind HCV therapy is the need of sustainable animal models that can help simulate in vivo conditions. We have assembled recent advances in animal models to study liver diseases for targeted therapy.

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“…Until recently, the lack of an appropriate preclinical small animal model has been the principal impediment to studying human adapted S. typhi pathogenesis and immunity. In recent years, humanized mice have been developed to understand the host-pathogen interactions of several human-specific viral pathogens such as Herpes simplex virus-2 (HSV-2), 18 Human Immunodeficiency Virus type 1 (HIV-1), 19 Hepatitis C virus 20 and Dengue virus. 21 In addition, immune response following tumor challenge has also been studied in this mouse model.…”

Section: Salmonella Typhi Develops Infection In His Micementioning

confidence: 99%