Inducing Hepatitis C Virus Resistance After Pig Liver Transplantation-A Proof of Concept of Liver Graft Modification Using Warm Ex Vivo Perfusion.
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.
Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada.
N
N
Goldaracena
Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada.
V N
VN
Spetzler
Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada.
J
J
Echeverri
Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada.
J M
JM
Kaths
Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Research, Toronto General Hospital, Toronto, ON, Canada.
V
V
Cherepanov
Roche Innovation Center, Copenhagen, Denmark.
R
R
Persson
RNA Medicines, San Diego, CA.
M R
MR
Hodges
Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Research, Toronto General Hospital, Toronto, ON, Canada.
H L A
HL
Janssen
Multi Organ Transplant Program-Department of Medicine, Toronto General Hospital, Toronto, ON, Canada.
N
N
Selzner
Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada.
D R
0000-0003-4468-8276
DR
Grant
Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Research, Toronto General Hospital, Toronto, ON, Canada.
J J
JJ
Feld
Multi Organ Transplant Program-Department of Surgery, Toronto General Hospital, Toronto, ON, Canada.
M
M
Selzner
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D005112:Extracorporeal Circulation; D016174:Hepacivirus / Q000235:genetics* / Q000302:isolation & purification; D006526:Hepatitis C / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D009841:Oligonucleotides / Q000627:therapeutic use*; D010477:Perfusion; D013552:Swine; D014779:Virus Replication / Q000235:genetics*
D000998:Antiviral Agents; D009841:Oligonucleotides; C581159:miravirsen
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/science; viral: hepatitis C