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New therapeutic opportunities for Hepatitis C based on small RNA

World Journal of Gastroenterology 2007年第33期13卷 4431-4436页

作者： Qiu-wei Pan Scot D Henry Bob J Scholte Hugo W Tilanus Harry LA Janssen luc jw van der laan Departments of Gastroenterology & Hepatology and Surgery Erasmus MC-University Medical Centre Rotterdam The Netherlands Department of Surgery Erasmus MC-University Medical Centre Rotterdam The Netherlands Department of Cell Biology Erasmus MC- University Medical Centre Rotterdam The Netherlands Department of Gastroenterology & Hepatology Erasmus MC-University Medical Centre Rotterdam The Netherlands

Hepatitis C virus （HCV） infection is one of the major causes of chronic liver disease, including cirrhosis and liver cancer and is therefore, the most common indication for liver transplantation. Conventional antiviral drugs such as pegylated interferon-alpha, taken in combination with ribavirin, represent a milestone in the therapy of this disease. However, due to different viral and host factors, clinical success can be achieved only in approximately half of patients, making urgent the requirement of exploiting alternative approaches for HCV therapy. Fortunately, recent advances in the understanding of HCV viral replication and host cell interactions have opened new possibilities for therapeutic intervention. The most recent technologies, such as small interference RNA mediated gene-silencing, antisense oligonucleotides （ASO）, or viral vector based gene delivery systems, have paved the way to develop novel therapeutic modalities for HCV. In this review, we outline the application of these technologies in the context of HCV therapy. In particular, we will focus on the newly defined role of cellular microRNA （miR-222） in viral replication and discuss its potential for HCV molecular therapy.

关键词： Hepatitis C virus therapy miR-122 RNAi Antisense oligonucleotides Viral vectors

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Interaction of immunosuppressants with HCV antivirals daclatasvir and asunaprevir: combined effects with mycophenolic acid

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World Journal of Transplantation 2018年第5期8卷 156-166页

作者： Petra E de Ruiter Yashna Gadjradj Robert J de Knegt Herold J Metselaar Jan NM Ijzermans luc jw van der laan Department of Surgery Erasmus MC-University Medical Center Department of Gastroenterology and Hepatology Erasmus MC-University Medical Center

AIM To investigate the specific effects of immunosuppressants on the antiviral action of daclatasvir and *** The antiviral activity of daclatasvir(DCV) and asunaprevir(ASV) combined with immunosuppressants was tested using two in vitro models for hepatitis C virus(HCV) *** Tacrolimus, rapamycin and cyclosporine did not negatively affect the antiviral action of DCV or ASV. Mycophenolic acid(MPA) showed additive antiviral effects combined with these direct acting antivirals(DAAs). MPA induces interferon-stimulated genes(ISGs) and is a potent GTP synthesis inhibitor. DCV or ASV did not induce ISGs expression nor affected ISG induction by MPA. Rather, the combined antiviral effect of MPA with DCV and ASV was partly mediated via inhibition of GTP *** Immunosuppressants do not negatively affect the antiviral activity of DAAs. MPA has additive effect on the antiviral action of DCV and ASV. This combined benefit needs to be confirmed in prospective clinical trials.

关键词： Immunosuppressant Hepatitis C Daclatasvir Asunaprevir Liver Transplantation

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m TOR signaling in liver regeneration: Rapamycin combined with growth factor treatment

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World Journal of Transplantation 2013年第3期3卷 36-47页

作者： Suomi MG Fouraschen Petra E de Ruiter Jaap Kwekkeboom Ron WF de Bruin Geert Kazemier Herold J Metselaar Hugo W Tilanus luc jw van der laan Jeroen de Jonge Department of Surgery and Laboratory of Experimental Transplantation and Intestinal Surgery Erasmus MC-University Medical Center 3015 CE Rotterdam The Netherlands Department of Gas-troenterology and Hepatology Erasmus MC-University Medical Center 3015 CE Rotterdam The Netherlands

AIM: To investigate the effects of mammalian target of rapamycin(mT OR) inhibition on liver regeneration and autophagy in a surgical resection ***: C57BL/6 mice were subjected to a 70% partial hepatectomy(PH) and treated intraperitoneally every 24 h with a combination of the m TOR inhibitor rapamycin(2.5 mg/kg per day) and the steroid dexamethasone(2.0 mg/kg per day) in phosphate bufferedsaline(PBS) or with PBS alone as vehicle control. In the immunosuppressant group, part of the group was treated subcutaneously 4 h prior to and 24 h after PH with a combination of human recombinant interleukin 6(IL-6; 500 μg/kg per day) and hepatocyte growth factor(HGF; 100 μg/kg per day) in PBS. Animals were sacrificed 2, 3 or 5 d after PH and liver tissue and blood were collected for further analysis. Immunohistochemical staining for 5-Bromo-2'-deoxyuridine(Brd U) was used to quantify hepatocyte proliferation. Western blotting was used to detect hepatic microtubule-associated protein 1 light chain 3(LC3)-Ⅱ protein expression as a marker for autophagy. Hepatic gene expression levels of proliferation-, inflammation- and angiogenesisrelated genes were examined by real-time reverse transcription-polymerase chain reaction and serum bilirubin and transaminase levels were analyzed at the clinical chemical core facility of the Erasmus MC-University Medical ***: m TOR inhibition significantly suppressed regeneration, shown by decreased hepatocyte proliferation(2% vs 12% Brd U positive hepatocyte nuclei at day 2, P < 0.01; 0.8% vs 1.4% at day 5, P = 0.02) and liver weight reconstitution(63% vs 76% of initial total liver weight at day 3, P = 0.04), and furthermore increased serum transaminase levels(aspartate aminotransferase 641 U/L vs 185 U/L at day 2, P = 0.02). Expression of the autophagy marker LC3-Ⅱ, which was reduced during normal liver regeneration, increased after mT OR inhibition(46% increase at day 2, P = 0.04). Hepatic gene expression showed an increased infl

关键词： Hepatocyte proliferation Autophagy Microtubule-associated protein 1 light chain 3 Partial hepatectomy Rapamycin

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Combined antiviral activity of interferon-α and RNA interference directed against hepatitis C without affecting vector delivery and gene silencing

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世界最新医学信息文摘 2017年第30期 281-281页

作者： Qiuwei Pan Scot D.Henry Herold J.Metselaar Bob Scholte Jaap Kwekkeboom Hugo W.Tilanus Harry L.A.Janssen luc J.W.van der laan

The current standard interferon-alpha(IFN-α)-based therapy for chronic hepatitis C virus(HCV) infection is only effective in approximately half of the patients,prompting the need for alternative *** interference(RNAi)represents novel approach to combat HCV by sequence-specific targeting of viral or host factors involved in *** of RNAi,however,may lead to therapeutic resistance by mutational escape of the ***,we proposed that combining lentiviral vector-mediated RNAi and IFN-a could be more effective and avoid therapeutic *** this study,we found that IFN-α treatment did not interfere with RNAi-mediated gene *** and IFN-α act independently on HCV replication showing combined antiviral activity when used simultaneously or *** ofmouse hepatocytes in vivo and in vitro was not effected by IFN-α *** conclusion,RNAi and IFN-a can be effectively combined without crossinterference and may represent a promising combinational strategy for the treatment of hepatitis C.

关键词： RNAi IFN-α Gene therapy Lentiviral vector HCV

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