Development of novel siRNA therapy to prevent hepatitis recurrence after the transplant by graft conditioning outside the body

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K15483
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Hokkaido University
• Principal Investigator: Taketomi Akinobu 北海道大学, 医学研究院, 教授 (70363364)
• Co-Investigator(Renkei-kenkyūsha): YOKOO Hideki 北海道大学, 大学病院, 助教 (70399947) ; GOTO Ryoichi 北海道大学, 大学病院, 助教 (10645287)
• Research Collaborator: FUJIYOSHI Masato
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 肝臓癌 / 外科 / 肝移植 / 臓器灌流 / 肝炎

Outline of Final Research Achievements

We explored a novel graft conditioning method based on siRNA gene silencing with an aim of preventing recurrence of viral hepatitis after orthotropic liver transplantation (OLT).
We established 1) mouse OLT model, 2) graft perfusion machine and method for mouse livers, 3) donor pre-conditioning method using siRNA, and 4) graft conditioning method by extracorporeal administration of siRNA. Donor pre-conditioning with siRNA targeting coagulation factor 7 inhibited the gene expression in the recipient body up to 72 hours after OLT when the procurement was performed 2 hours or longer after siRNA administration to the donor. Extracorporeal siRNA treatment showed strong attenuated effect in machine perfusion at 25°but ineffective at 4°C. Therefore, machine perfusion at 37°C seemed to be necessary to achieve the siRNA treatment. Here, we obtained the proof of concept that pre-transplant graft conditioning with siRNA is a therapeutic method against post-OLT recurrence of viral hepatitis.

Free Research Field

肝臓外科