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Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery
Anti-cytokine therapies have substantially improved the treatment of inflammatory and autoimmune diseases. Cytokine-targeting drugs are usually biologics such as antibodies or other engineered proteins. Production of biologics, however, is complex and intricate and therefore expensive which might li...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589789/ https://www.ncbi.nlm.nih.gov/pubmed/26423228 http://dx.doi.org/10.1038/srep14685 |
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author | Görtz, Dieter Braun, Gerald S. Maruta, Yuichi Djudjaj, Sonja van Roeyen, Claudia R. Martin, Ina V. Küster, Andrea Schmitz-Van de Leur, Hildegard Scheller, Jürgen Ostendorf, Tammo Floege, Jürgen Müller-Newen, Gerhard |
author_facet | Görtz, Dieter Braun, Gerald S. Maruta, Yuichi Djudjaj, Sonja van Roeyen, Claudia R. Martin, Ina V. Küster, Andrea Schmitz-Van de Leur, Hildegard Scheller, Jürgen Ostendorf, Tammo Floege, Jürgen Müller-Newen, Gerhard |
author_sort | Görtz, Dieter |
collection | PubMed |
description | Anti-cytokine therapies have substantially improved the treatment of inflammatory and autoimmune diseases. Cytokine-targeting drugs are usually biologics such as antibodies or other engineered proteins. Production of biologics, however, is complex and intricate and therefore expensive which might limit therapeutic application. To overcome this limitation we developed a strategy that involves the design of an optimized, monogenic cytokine inhibitor and the protein producing capacity of the host. Here, we engineered and characterized a receptor fusion protein, mIL-6-RFP-Fc, for the inhibition of interleukin-6 (IL-6), a well-established target in anti-cytokine therapy. Upon application in mice mIL-6-RFP-Fc inhibited IL-6-induced activation of the transcription factor STAT3 and ERK1/2 kinases in liver and kidney. mIL-6-RFP-Fc is encoded by a single gene and therefore most relevant for gene transfer approaches. Gene transfer through hydrodynamic plasmid delivery in mice resulted in hepatic production and secretion of mIL-6-RFP-Fc into the blood in considerable amounts, blocked hepatic acute phase protein synthesis and improved kidney function in an ischemia and reperfusion injury model. Our study establishes receptor fusion proteins as promising agents in anti-cytokine therapies through gene therapeutic approaches for future targeted and cost-effective treatments. The strategy described here is applicable for many cytokines involved in inflammatory and other diseases. |
format | Online Article Text |
id | pubmed-4589789 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-45897892015-10-13 Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery Görtz, Dieter Braun, Gerald S. Maruta, Yuichi Djudjaj, Sonja van Roeyen, Claudia R. Martin, Ina V. Küster, Andrea Schmitz-Van de Leur, Hildegard Scheller, Jürgen Ostendorf, Tammo Floege, Jürgen Müller-Newen, Gerhard Sci Rep Article Anti-cytokine therapies have substantially improved the treatment of inflammatory and autoimmune diseases. Cytokine-targeting drugs are usually biologics such as antibodies or other engineered proteins. Production of biologics, however, is complex and intricate and therefore expensive which might limit therapeutic application. To overcome this limitation we developed a strategy that involves the design of an optimized, monogenic cytokine inhibitor and the protein producing capacity of the host. Here, we engineered and characterized a receptor fusion protein, mIL-6-RFP-Fc, for the inhibition of interleukin-6 (IL-6), a well-established target in anti-cytokine therapy. Upon application in mice mIL-6-RFP-Fc inhibited IL-6-induced activation of the transcription factor STAT3 and ERK1/2 kinases in liver and kidney. mIL-6-RFP-Fc is encoded by a single gene and therefore most relevant for gene transfer approaches. Gene transfer through hydrodynamic plasmid delivery in mice resulted in hepatic production and secretion of mIL-6-RFP-Fc into the blood in considerable amounts, blocked hepatic acute phase protein synthesis and improved kidney function in an ischemia and reperfusion injury model. Our study establishes receptor fusion proteins as promising agents in anti-cytokine therapies through gene therapeutic approaches for future targeted and cost-effective treatments. The strategy described here is applicable for many cytokines involved in inflammatory and other diseases. Nature Publishing Group 2015-10-01 /pmc/articles/PMC4589789/ /pubmed/26423228 http://dx.doi.org/10.1038/srep14685 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Görtz, Dieter Braun, Gerald S. Maruta, Yuichi Djudjaj, Sonja van Roeyen, Claudia R. Martin, Ina V. Küster, Andrea Schmitz-Van de Leur, Hildegard Scheller, Jürgen Ostendorf, Tammo Floege, Jürgen Müller-Newen, Gerhard Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery |
title | Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery |
title_full | Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery |
title_fullStr | Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery |
title_full_unstemmed | Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery |
title_short | Anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery |
title_sort | anti-interleukin-6 therapy through application of a monogenic protein inhibitor via gene delivery |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589789/ https://www.ncbi.nlm.nih.gov/pubmed/26423228 http://dx.doi.org/10.1038/srep14685 |
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