Use of RNA interference to minimize ischemia reperfusion injury

RNA interference (RNAi) is an endogenous mechanism of cellular RNA control through degradation of specific messenger RNA sequences. This process of gene silencing may be exploited by the use of small interfering RNA (siRNA) to mediate precise control of targeted cellular functions. The nature of transplantation leads invariably to tissue injury, as organs are damaged by the loss of blood supply and resultant ischemia associated with the procurement procedure. Upon reperfusion, an inflammatory program is activated, and subsequent injury results in delayed graft function and, potentially, organ failure. Many of the molecular components in ischemia-reperfusion injury (IRI) have been identified, but effective therapeutics are not currently available. Accumulating evidence supports a role for siRNA in controlling IRI, as siRNA is specific, relatively low in toxicity, and limited in duration of effect. The capacity of siRNA to control IRI-related transcription factors, cell death and apoptosis, complement factors, and oxidative stress molecules supports the concept that RNAi-based therapeutics represent a novel and promising strategy for the control of IRI. However, there are issues of RNAi strategies, including siRNA design, “off-target” effects, and delivery that merit consideration in approaching IRI with gene silencing. This review will provide an overview of current concepts in RNAi and the potential application to IRI in solid organ transplantation.