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Lookup NU author(s): Emily Thompson, Dr Avinash Sewpaul, Lucy BatesORCiD, Dr Sam Tingle, Dr Aldi Situmorang, Shameem Sultanali Ladak, Chloe Connelly, Professor Simi Ali, Professor Colin Wilson, Professor Neil SheerinORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
Normothermic machine perfusion (NMP) is a novel clinical approach to overcome the limitations of traditional hypothermic organ preservation. NMP can be used to assess and recondition organs prior to transplant and is the subject of clinical trials in solid organ transplantation. In addition, NMP provides an opportunity to deliver therapeutic agents directly to the organ thus avoiding many limitations associated with systemic treatment of the recipient. We report the delivery of oligonucleotide-based therapy to human kidneys during NMP, in this case to target microRNA function (antagomir). An antagomir targeting mir-24-3p localised to the endothelium and proximal tubular epithelium. Endosomal uptake during NMP conditions facilitated antagomir co-localisation with proteins involved in the RNA-induced silencing complex (RISC) and demonstrated engagement of the miRNA target. This pattern of uptake was not seen during cold perfusion. Targeting mir-24-3p action increased expression of genes controlled by this microRNA, including heme oxygenase-1 and sphingosine-1-phosphate receptor 1. The expression of genes not under the control of mir-24-3p was unchanged, indicating specificity of the antagomir effect. In summary, this is the first report of ex-vivo gymnotic delivery of oligonucleotide to the human kidney and demonstrates that NMP provides the platform to bind and block detrimental microRNAs in donor kidneys prior to transplantation.
Author(s): Thompson ER, Sewpaul A, Figuereido R, Bates L, Tingle SJ, Ferdinand JR, Situmorang GR, Ladak SS, Connelly CM, Hosgood SA, Nicholson ML, Clatworthy MR, Ali S, Wilson CH, Sheerin NS
Publication type: Article
Publication status: Published
Journal: American Journal of Transplantation
Year: 2022
Volume: 22
Issue: 4
Pages: 1088-1100
Print publication date: 01/04/2022
Online publication date: 21/12/2021
Acceptance date: 14/02/2021
Date deposited: 04/01/2022
ISSN (electronic): 1600-6143
Publisher: Wiley
URL: https://doi.org/10.1111/ajt.16929
DOI: 10.1111/ajt.16929
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