Immunomodulation of the donor lung with CRISPR-mediated activation of IL-10 expression
Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved..
BACKGROUND: Inflammatory injury in the donor lung remains a persistent challenge in lung transplantation that limits donor organ usage and post-transplant outcomes. Inducing immunomodulatory capacity in donor organs could address this unsolved clinical problem. We sought to apply clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas) technologies to the donor lung to fine-tune immunomodulatory gene expression, exploring for the first time the therapeutic use of CRISPR-mediated transcriptional activation in the whole donor lung.
METHODS: We explored the feasibility of CRISPR-mediated transcriptional upregulation of interleukin 10 (IL-10), a key immunomodulatory cytokine, in vitro and in vivo. We first evaluated the potency, titratability, and multiplexibility of the gene activation in rat and human cell lines. Next, in vivo CRISPR-mediated IL-10 activation was characterized in rat lungs. Finally, the IL-10-activated donor lungs were transplanted into recipient rats to assess the feasibility in a transplant setting.
RESULTS: The targeted transcriptional activation induced robust and titrable IL-10 upregulation in vitro. The combination of guide RNAs also facilitated multiplex gene modulation, that is, simultaneous activation of IL-10 and IL1 receptor antagonist. In vivo profiling demonstrated that adenoviral delivery of Cas9-based activators to the lung was feasible with the use of immunosuppression, which is routinely applied to organ transplant recipients. The transcriptionally modulated donor lungs retained IL-10 upregulation in isogeneic and allogeneic recipients.
CONCLUSIONS: Our findings highlight the potential of CRISPR epigenome editing to improve lung transplant outcomes by creating a more favorable immunomodulatory environment in the donor organ, a paradigm that may be extendable to other organ transplants.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:42 |
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| Enthalten in: |
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation - 42(2023), 10 vom: 12. Okt., Seite 1363-1377 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mesaki, Kumi [VerfasserIn] |
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| Links: |
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| Themen: |
130068-27-8 |
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| Anmerkungen: |
Date Completed 26.09.2023 Date Revised 03.10.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.healun.2023.06.001 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM358173760 |
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| 100 | 1 | |a Mesaki, Kumi |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Immunomodulation of the donor lung with CRISPR-mediated activation of IL-10 expression |
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| 500 | |a Date Revised 03.10.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a BACKGROUND: Inflammatory injury in the donor lung remains a persistent challenge in lung transplantation that limits donor organ usage and post-transplant outcomes. Inducing immunomodulatory capacity in donor organs could address this unsolved clinical problem. We sought to apply clustered regularly interspaced short palindromic repeats (CRISPR)-associated (Cas) technologies to the donor lung to fine-tune immunomodulatory gene expression, exploring for the first time the therapeutic use of CRISPR-mediated transcriptional activation in the whole donor lung | ||
| 520 | |a METHODS: We explored the feasibility of CRISPR-mediated transcriptional upregulation of interleukin 10 (IL-10), a key immunomodulatory cytokine, in vitro and in vivo. We first evaluated the potency, titratability, and multiplexibility of the gene activation in rat and human cell lines. Next, in vivo CRISPR-mediated IL-10 activation was characterized in rat lungs. Finally, the IL-10-activated donor lungs were transplanted into recipient rats to assess the feasibility in a transplant setting | ||
| 520 | |a RESULTS: The targeted transcriptional activation induced robust and titrable IL-10 upregulation in vitro. The combination of guide RNAs also facilitated multiplex gene modulation, that is, simultaneous activation of IL-10 and IL1 receptor antagonist. In vivo profiling demonstrated that adenoviral delivery of Cas9-based activators to the lung was feasible with the use of immunosuppression, which is routinely applied to organ transplant recipients. The transcriptionally modulated donor lungs retained IL-10 upregulation in isogeneic and allogeneic recipients | ||
| 520 | |a CONCLUSIONS: Our findings highlight the potential of CRISPR epigenome editing to improve lung transplant outcomes by creating a more favorable immunomodulatory environment in the donor organ, a paradigm that may be extendable to other organ transplants | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CRISPR | |
| 650 | 4 | |a IL-10 | |
| 650 | 4 | |a dSaCas9-VPR | |
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| 650 | 4 | |a lung transplant | |
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| 700 | 1 | |a Juvet, Stephen |e verfasserin |4 aut | |
| 700 | 1 | |a Yeung, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Guan, Zehong |e verfasserin |4 aut | |
| 700 | 1 | |a Wilson, Gavin W |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Jim |e verfasserin |4 aut | |
| 700 | 1 | |a Davidson, Alan R |e verfasserin |4 aut | |
| 700 | 1 | |a Kleinstiver, Benjamin P |e verfasserin |4 aut | |
| 700 | 1 | |a Cypel, Marcelo |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Mingyao |e verfasserin |4 aut | |
| 700 | 1 | |a Keshavjee, Shaf |e verfasserin |4 aut | |
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