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...

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Bibliographic Details
Published in:Molecular therapy. Nucleic acids 2019-06, Vol.16, p.194-205
Main Authors: 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.
Format: Article
Language:English
Subjects:
Allergens
Alveoli
Bioavailability
CD11c antigen
delivery
Dendritic cells
Design
Epithelial cells
Experiments
Gene expression
Immune response (cell-mediated)
Inflammation
Internalization
Ligands
Liver
lung
Lungs
Lymphocytes T
Macrophages
Metabolism
mRNA
Oligonucleotides
Pathology
RNA-mediated interference
RNAi
siRNA
Software
Statistical analysis
Trachea
Tropism
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Summary: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.
ISSN:2162-2531
2162-2531
DOI:10.1016/j.omtn.2019.02.013