MicroRNA antagonist therapy during normothermic machine perfusion of donor kidneys
© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons..
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 localized to the endothelium and proximal tubular epithelium. Endosomal uptake during NMP conditions facilitated antagomir co-localization 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
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| Enthalten in: |
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons - 22(2022), 4 vom: 18. Apr., Seite 1088-1100 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Thompson, Emily R [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.04.2022 Date Revised 24.01.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/ajt.16929 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM334688949 |
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| 100 | 1 | |a Thompson, Emily R |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a MicroRNA antagonist therapy during normothermic machine perfusion of donor kidneys |
| 264 | 1 | |c 2022 | |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022 The American Society of Transplantation and the American Society of Transplant Surgeons. | ||
| 520 | |a 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 localized to the endothelium and proximal tubular epithelium. Endosomal uptake during NMP conditions facilitated antagomir co-localization 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a basic (laboratory) research/science | |
| 650 | 4 | |a gene therapy | |
| 650 | 4 | |a ischemia reperfusion injury (IRI) | |
| 650 | 4 | |a kidney transplantation/nephrology | |
| 650 | 4 | |a molecular biology: micro RNA | |
| 650 | 4 | |a organ perfusion and preservation | |
| 650 | 4 | |a translational research/science | |
| 650 | 7 | |a MicroRNAs |2 NLM | |
| 700 | 1 | |a Sewpaul, Avinash |e verfasserin |4 aut | |
| 700 | 1 | |a Figuereido, Rodrigo |e verfasserin |4 aut | |
| 700 | 1 | |a Bates, Lucy |e verfasserin |4 aut | |
| 700 | 1 | |a Tingle, Samuel J |e verfasserin |4 aut | |
| 700 | 1 | |a Ferdinand, John R |e verfasserin |4 aut | |
| 700 | 1 | |a Situmorang, Gerhard R |e verfasserin |4 aut | |
| 700 | 1 | |a Ladak, Shameem S |e verfasserin |4 aut | |
| 700 | 1 | |a Connelly, Chloe M |e verfasserin |4 aut | |
| 700 | 1 | |a Hosgood, Sarah A |e verfasserin |4 aut | |
| 700 | 1 | |a Nicholson, Michael L |e verfasserin |4 aut | |
| 700 | 1 | |a Clatworthy, Menna R |e verfasserin |4 aut | |
| 700 | 1 | |a Ali, Simi |e verfasserin |4 aut | |
| 700 | 1 | |a Wilson, Colin H |e verfasserin |4 aut | |
| 700 | 1 | |a Sheerin, Neil S |e verfasserin |4 aut | |
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