RNAi-based modulation of IFN-γ signaling in skin
Published by Elsevier Inc..
Aberrant activation of interferon (IFN)-γ signaling plays a key role in several autoimmune skin diseases, including lupus erythematosus, alopecia areata, vitiligo, and lichen planus. Here, we identify fully chemically modified small interfering RNAs (siRNAs) that silence the ligand binding chain of the IFN-γ receptor (IFNGR1), for the modulation of IFN-γ signaling. Conjugating these siRNAs to docosanoic acid (DCA) enables productive delivery to all major skin cell types local to the injection site, with a single dose of injection supporting effective IFNGR1 protein reduction for at least 1 month in mice. In an ex vivo model of IFN-γ signaling, DCA-siRNA efficiently inhibits the induction of IFN-γ-inducible chemokines, CXCL9 and CXCL10, in skin biopsies from the injection site. Our data demonstrate that DCA-siRNAs can be engineered for functional gene silencing in skin and establish a path toward siRNA treatment of autoimmune skin diseases.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Molecular therapy : the journal of the American Society of Gene Therapy - 30(2022), 8 vom: 03. Aug., Seite 2709-2721 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tang, Qi [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.08.2022 Date Revised 04.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ymthe.2022.04.019 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM340065508 |
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| 245 | 1 | 0 | |a RNAi-based modulation of IFN-γ signaling in skin |
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| 520 | |a Published by Elsevier Inc. | ||
| 520 | |a Aberrant activation of interferon (IFN)-γ signaling plays a key role in several autoimmune skin diseases, including lupus erythematosus, alopecia areata, vitiligo, and lichen planus. Here, we identify fully chemically modified small interfering RNAs (siRNAs) that silence the ligand binding chain of the IFN-γ receptor (IFNGR1), for the modulation of IFN-γ signaling. Conjugating these siRNAs to docosanoic acid (DCA) enables productive delivery to all major skin cell types local to the injection site, with a single dose of injection supporting effective IFNGR1 protein reduction for at least 1 month in mice. In an ex vivo model of IFN-γ signaling, DCA-siRNA efficiently inhibits the induction of IFN-γ-inducible chemokines, CXCL9 and CXCL10, in skin biopsies from the injection site. Our data demonstrate that DCA-siRNAs can be engineered for functional gene silencing in skin and establish a path toward siRNA treatment of autoimmune skin diseases | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a CXCL9/10/11 chemokines | |
| 650 | 4 | |a IFN-γ signaling | |
| 650 | 4 | |a RNAi therapeutics | |
| 650 | 4 | |a autoimmune disorders | |
| 650 | 4 | |a immunomodulatory drugs | |
| 650 | 4 | |a preclinical drug development | |
| 650 | 4 | |a siRNA delivery | |
| 650 | 4 | |a skin immunology | |
| 650 | 7 | |a Chemokine CXCL10 |2 NLM | |
| 650 | 7 | |a RNA, Small Interfering |2 NLM | |
| 650 | 7 | |a Interferon-gamma |2 NLM | |
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| 700 | 1 | |a Sousa, Jacquelyn |e verfasserin |4 aut | |
| 700 | 1 | |a Echeverria, Dimas |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Xueli |e verfasserin |4 aut | |
| 700 | 1 | |a Hsueh, Ying-Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Afshari, Khashayar |e verfasserin |4 aut | |
| 700 | 1 | |a MeHugh, Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a Cooper, David A |e verfasserin |4 aut | |
| 700 | 1 | |a Vangjeli, Lorenc |e verfasserin |4 aut | |
| 700 | 1 | |a Monopoli, Kathryn |e verfasserin |4 aut | |
| 700 | 1 | |a Okamura, Ken |e verfasserin |4 aut | |
| 700 | 1 | |a Biscans, Annabelle |e verfasserin |4 aut | |
| 700 | 1 | |a Clauss, Adam |e verfasserin |4 aut | |
| 700 | 1 | |a Harris, John E |e verfasserin |4 aut | |
| 700 | 1 | |a Khvorova, Anastasia |e verfasserin |4 aut | |
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