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MicroRNA antagonist therapy during normothermic machine perfusion of donor kidneys

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, Colin Wilson, Professor Neil SheerinORCiD

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Wiley, 2021.

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Abstract

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.


Publication metadata

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: 2021

Pages: epub ahead of print

Online publication date: 21/12/2021

Acceptance date: 21/12/2021

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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