Delivering siRNA Compounds During HOPE to Modulate Organ Function: A Proof-of-concept Study in a Rat Liver Transplant Model

Eliano Bonaccorsi-Riani, Andrew R. Gillooly, Samuele Iesari, Isabel M. A. Bruggenwirth, Chantal M. Ferguson, Mina Komuta, Daela Xhema, Aurelie Daumerie, Louis Maistriaux, Henri Leuvenink, Jerzy Kupiec-Weglinski, Robert J. Porte, Anastasia Khvorova, David R. Cave, Pierre Gianello, Paulo N. Martins*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)
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Abstract

Background. Apoptosis contributes to the severity of ischemia-reperfusion injury (IRI), limiting the use of extended criteria donors in liver transplantation (LT). Machine perfusion has been proposed as a platform to administer specific therapies to improve graft function. Alternatively, the inhibition of genes associated with apoptosis during machine perfusion could alleviate IRI post-LT. The aim of the study was to investigate whether inhibition of an apoptosis-associated gene (FAS) using a small interfering RNA (siRNA) approach could alleviate IRI in a rat LT model. Methods. In 2 different experimental protocols, FASsiRNA (500 mu g) was administered to rat donors 2h before organ procurement, followed by 22h of static cold storage, (SCS) or was added to the perfusate during 1h of ex situ hypothermic oxygenated perfusion (HOPE) to livers previously preserved for 4h in SCS. Results. Transaminase levels were significantly lower in the SCS-FASsiRNA group at 24h post-LT. Proinflammatory cytokines (interleukin-2, C-X-C motif chemokine 10, tumor necrosis factor alpha, and interferon gamma) were significantly decreased in the SCS-FASsiRNA group, whereas the interleukin-10 anti-inflammatory cytokine was significantly increased in the HOPE-FASsiRNA group. Liver absorption of FASsiRNA after HOPE session was demonstrated by confocal microscopy; however, no statistically significant differences on the apoptotic index, necrosis levels, and FAS protein transcription between treated and untreated groups were observed. Conclusions. FAS inhibition through siRNA therapy decreases the severity of IRI after LT in a SCS protocol; however the association of siRNA therapy with a HOPE perfusion model is very challenging. Future studies using better designed siRNA compounds and appropriate doses are required to prove the siRNA therapy effectiveness during liver HOPE liver perfusion.

Original languageEnglish
Pages (from-to)1565-1576
Number of pages12
JournalTransplantation
Volume106
Issue number8
DOIs
Publication statusPublished - Aug-2022

Keywords

  • ISCHEMIA-REPERFUSION INJURY
  • MACHINE PERFUSION
  • RNA INTERFERENCE
  • CELL-DEATH
  • MECHANISMS
  • APOPTOSIS
  • GRAFT
  • COLD
  • PROTECTS
  • WARM

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