Inducing Hepatitis C Virus Resistance After Pig Liver Transplantation-A Proof of Concept of Liver Graft Modification Using Warm Ex Vivo Perfusion

被引：69

作者：

Goldaracena, N. ^{[1
]}

Spetzler, V. N. ^{[1
]}

Echeverri, J. ^{[1
]}

Kaths, J. M. ^{[1
]}

Cherepanov, V. ^{[2
]}

Persson, R. ^{[3
]}

Hodges, M. R. ^{[4
]}

Janssen, H. L. A. ^{[2
]}

Selzner, N. ^{[5
]}

Grant, D. R. ^{[1
]}

Feld, J. J. ^{[2
]}

Selzner, M. ^{[1
]}

机构：

[1] Toronto Gen Hosp, Dept Surg, Multi Organ Transplant Program, Toronto, ON, Canada

[2] Toronto Gen Hosp, Sandra Rotman Ctr Global Res, Toronto Ctr Liver Dis, Toronto, ON, Canada

[3] Roche Innovat Ctr, Copenhagen, Denmark

[4] RNA Med, San Diego, CA USA

[5] Toronto Gen Hosp, Dept Med, Multi Organ Transplant Program, Toronto, ON, Canada

来源：

AMERICAN JOURNAL OF TRANSPLANTATION | 2017年 / 17卷 / 04期

关键词：

animal models: porcine; basic (laboratory) research; science; infection and infectious agents; liver transplantation; hepatology; molecular biology: micro RNA; organ perfusion and preservation; organ transplantation in general; translational research; viral: hepatitis C; BILE-DUCT INJURY; PRESERVATION; MIR-122; HCV; DASABUVIR;

D O I：

10.1111/ajt.14100

中图分类号：

R61 [外科手术学];

学科分类号：

摘要：

Normothermic ex vivo liver perfusion (NEVLP) offers the potential to optimize graft function prior to liver transplantation (LT). Hepatitis C virus (HCV) is dependent on the presence of miRNA(microRNA)-122. Miravirsen, a locked-nucleic acid oligonucleotide, sequesters miR-122 and inhibits HCV replication. The aim of this study was to assess the efficacy of delivering miravirsen during NEVLP to inhibit miR-122 function in a pig LT model. Pig livers were treated with miravirsen during NEVLP or cold storage (CS). Miravirsen absorption, miR-122 sequestration, and miR-122 target gene derepression were determined before and after LT. The effect of miravirsen treatment on HCV infection of hepatoma cells was also assessed. NEVLP improved miravirsen uptake versus CS. Significant miR-122 sequestration and miR-122 target gene derepression were seen with NEVLP but not with CS. In vitro data confirmed miravirsen suppression of HCV replication after established infection and prevented HCV infection with pretreatment of cells, analogous to the pretreatment of grafts in the transplant setting. In conclusion, miravirsen delivery during NEVLP is a potential strategy to prevent HCV reinfection after LT. This is the first large-animal study to provide proof of concept for using NEVLP to modify and optimize liver grafts for transplantation.

引用

页码：970 / 978

页数：9

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