Gene Silencing With siRNA (RNA Interference): A New Therapeutic Option During Ex Vivo Machine Liver Perfusion Preservation

Abstract

RNA interference (RNAi) is a natural process of posttranscriptional gene regulation that has raised a lot of attention culminating with the Nobel Prize in Medicine in 2006. RNAi‐based therapeutics have been tested in experimental transplantation to reduce ischemia/reperfusion injury (IRI) with success. Modulation of genes of the innate immune system, as well as apoptotic genes, and those involved in the nuclear factor kappa B pathways can reduce liver injury in rodent liver pedicle clamping and transplantation models of IRI. However, in vivo use of RNAi faces limitations regarding the method of administration, uptake, selectivity, and stability. Machine perfusion preservation, a more recent alternative approach for liver preservation showing superior results to static cold preservation, could be used as a platform for gene interference therapeutics. Our group was the first to demonstrate uptake of small interfering RNA (siRNA) during liver machine preservation under both normothermic and hypothermic perfusion. Administering siRNA in the perfusion solution during ex vivo machine preservation has several advantages, including more efficient delivery, lower doses and cost‐saving, and none/fewer side effects to other organs. Recently, the first RNAi drug was approved by the US Food and Drug Administration for clinical use, opening a new avenue for new drugs with different clinical applications. RNAi has the potential to have transformational therapeutic applications in several areas of medicine including transplantation. We believe that machine preservation offers great potential to be the ideal delivery method of siRNA to the liver graft, and future studies should be initiated to improve the clinical applicability of RNAi in solid organ transplantation.

Machine Perfusion: Cold versus Warm, versus Neither. Update on Clinical Trials

“…As such, genetic modulation therapies can be administered during MP to improve post-LT outcome. [85][86][87][88] In the future, the development of nanoparticles may be translated into clinical use with the potential to mitigate organ damage through a variety of mechanisms. 89 More studies are needed to address these strategies.…”

The future of organ perfusion and re‐conditioning

“…Thijssen et al . have demonstrated that small interfering RNA, together with lipid‐based nanoparticles, successfully silenced the apoptotic gene p53 in a murine NMP model.…”

“…Furthermore, one can be confident that the therapeutic intervention can be successfully delivered to the target organ, without other systemic uptake and associated effects. Thijssen et al [66] have demonstrated that small interfering RNA, together with lipid-based nanoparticles, successfully silenced the apoptotic gene p53 in a murine NMP model.…”

RNA interference therapeutics in organ transplantation: The dawn of a new era

“…In the case of organ transplantation in particular, ex situ machine perfusion can be an attractive approach for targeted siRNA delivery to the organ during preservation. 8 It prevents filtration by other organs, enzymatic degradation of siRNA in the serum, and off-target effects. In addition, it is clinically more applicable, because RNAi treatment of individual organs can take place after organ procurement, instead of treating the donor systemically.…”

“…In the case of organ transplantation in particular, ex situ machine perfusion can be an attractive approach for targeted siRNA delivery to the organ during preservation . It prevents filtration by other organs, enzymatic degradation of siRNA in the serum, and off‐target effects.…”