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Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation
Clinical application of siRNA-based therapeutics outside of the liver has been hindered by the inefficient delivery of siRNA effector molecules into extra-hepatic organs and cells of interest. To understand the parameters that enable RNAi activity in vivo, it is necessary to develop a systematic app...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426712/ https://www.ncbi.nlm.nih.gov/pubmed/30901578 http://dx.doi.org/10.1016/j.omtn.2019.02.013 |
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author | Ng, Bruce Cash-Mason, Tanesha Wang, Yi Seitzer, Jessica Burchard, Julja Brown, Duncan Dudkin, Vadim Davide, Joseph Jadhav, Vasant Sepp-Lorenzino, Laura Cejas, Pedro J. |
author_facet | Ng, Bruce Cash-Mason, Tanesha Wang, Yi Seitzer, Jessica Burchard, Julja Brown, Duncan Dudkin, Vadim Davide, Joseph Jadhav, Vasant Sepp-Lorenzino, Laura Cejas, Pedro J. |
author_sort | Ng, Bruce |
collection | PubMed |
description | Clinical application of siRNA-based therapeutics outside of the liver has been hindered by the inefficient delivery of siRNA effector molecules into extra-hepatic organs and cells of interest. To understand the parameters that enable RNAi activity in vivo, it is necessary to develop a systematic approach to identify which cells within a tissue are permissive to oligonucleotide internalization and activity. In the present study, we evaluate the distribution and activity within the lung of chemically stabilized siRNA to characterize cell-type tropism and structure-activity relationship. We demonstrate intratracheal delivery of fully modified siRNA for RNAi-mediated target knockdown in lung CD11c(+) cells (dendritic cells, alveolar macrophages) and alveolar epithelial cells. Finally, we use an allergen-induced model of lung inflammation to demonstrate the capacity of inhaled siRNA to induce target knockdown in dendritic cells and ameliorate lung pathology. |
format | Online Article Text |
id | pubmed-6426712 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-64267122019-04-01 Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation Ng, Bruce Cash-Mason, Tanesha Wang, Yi Seitzer, Jessica Burchard, Julja Brown, Duncan Dudkin, Vadim Davide, Joseph Jadhav, Vasant Sepp-Lorenzino, Laura Cejas, Pedro J. Mol Ther Nucleic Acids Article Clinical application of siRNA-based therapeutics outside of the liver has been hindered by the inefficient delivery of siRNA effector molecules into extra-hepatic organs and cells of interest. To understand the parameters that enable RNAi activity in vivo, it is necessary to develop a systematic approach to identify which cells within a tissue are permissive to oligonucleotide internalization and activity. In the present study, we evaluate the distribution and activity within the lung of chemically stabilized siRNA to characterize cell-type tropism and structure-activity relationship. We demonstrate intratracheal delivery of fully modified siRNA for RNAi-mediated target knockdown in lung CD11c(+) cells (dendritic cells, alveolar macrophages) and alveolar epithelial cells. Finally, we use an allergen-induced model of lung inflammation to demonstrate the capacity of inhaled siRNA to induce target knockdown in dendritic cells and ameliorate lung pathology. American Society of Gene & Cell Therapy 2019-02-26 /pmc/articles/PMC6426712/ /pubmed/30901578 http://dx.doi.org/10.1016/j.omtn.2019.02.013 Text en © 2019 The American Society of Gene and Cell Therapy. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Ng, Bruce Cash-Mason, Tanesha Wang, Yi Seitzer, Jessica Burchard, Julja Brown, Duncan Dudkin, Vadim Davide, Joseph Jadhav, Vasant Sepp-Lorenzino, Laura Cejas, Pedro J. Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation |
title | Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation |
title_full | Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation |
title_fullStr | Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation |
title_full_unstemmed | Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation |
title_short | Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation |
title_sort | intratracheal administration of sirna triggers mrna silencing in the lung to modulate t cell immune response and lung inflammation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426712/ https://www.ncbi.nlm.nih.gov/pubmed/30901578 http://dx.doi.org/10.1016/j.omtn.2019.02.013 |
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