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(Circulation. 2009;120:1099-1107.)
© 2009 American Heart Association, Inc.

Transplantation

Novel Small Interfering RNA–Containing Solution Protecting Donor Organs in Heart Transplantation

Xiufen Zheng, PhD; Dameng Lian, MD; Arthur Wong, BS; Michael Bygrave, MS; Thomas E. Ichim, PhD; Mahdieh Khoshniat, PhD; Xusheng Zhang, MD; Hongtao Sun, MD; Tobias De Zordo, MD; James C. Lacefield, PhD; Bertha Garcia, MD; Anthony M. Jevnikar, MD; Wei-Ping Min, MD, PhD

From the Departments of Surgery, Pathology, Electrical and Computer Engineering, and Medical Biophysics (X.Z., D.L., A.W., T.E.I., M.K., X.Z., H.S., J.C.L., B.G., A.M.J., W.M.) and Robarts Research Institute (M.B., T.D.Z., J.C.L.), University of Western Ontario, London, Ontario, Canada; Multi-Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada (X. Zheng, D.L., B.G., A.M.J., W.M.); and Medistem Laboratories, San Diego, Calif (T.E.I.).

Reprint requests to Dr Wei-Ping Min, 339 Windermere Rd, University Hospital C9–136, London, Ontario, N6A 5A5, Canada. E-mail weiping.min{at}uwo.ca

Received April 18, 2008; accepted July 6, 2009.

Background— Ischemia/reperfusion injury is a major factor in graft quality and subsequent function in the transplantation setting. We hypothesize that the process of RNA interference may be used to "engineer" a graft to suppress expression of genes associated with inflammation, apoptosis, and complement, which are believed to cause ischemia/reperfusion injury. Such manipulation of pathological gene expression may be performed by treatment of the graft ex vivo with small interfering RNA (siRNA) as part of the preservation procedure.

Methods and Results— Heart grafts from BALB/c mice were preserved in UW solution (control) or UW solution containing siRNAs targeting tumor necrosis factor-, C3, and Fas genes (siRNA solution) at 4°C for 48 hours and subsequently transplanted into syngeneic recipients. Tumor necrosis factor-, C3, and Fas genes were elevated by ischemia/reperfusion injury after 48 hours of preservation in UW solution. Preservation in siRNA solution knocked down gene expression at the level of messenger RNA and protein in the grafts after transplantation. All grafts preserved in siRNA solution showed strong contraction, whereas grafts preserved in control solution demonstrated no detectable contraction by high-frequency ultrasound scanning. siRNA solution–treated organs exhibited improved histology and diminished neutrophil and lymphocyte infiltration compared with control solution–treated organs. Furthermore, the treated heart grafts retained strong beating up to the end of the observation period (>100 days), whereas all control grafts lost function within 8 days.

Conclusion— Incorporation of siRNA into organ storage solution is a feasible and effective method of attenuating ischemia/reperfusion injury, protecting cardiac function, and prolonging graft survival.

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