Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation

Bruce Ng; Tanesha Cash-Mason; Yi Wang; Jessica Seitzer; Julja Burchard; Duncan Brown; Vadim Dudkin; Joseph Davide; Vasant Jadhav; Laura Sepp-Lorenzino; Pedro J Cejas

doi:10.1016/j.omtn.2019.02.013

Intratracheal Administration of siRNA Triggers mRNA Silencing in the Lung to Modulate T Cell Immune Response and Lung Inflammation

Mol Ther Nucleic Acids. 2019 Jun 7:16:194-205. doi: 10.1016/j.omtn.2019.02.013. Epub 2019 Feb 26.

Authors

Affiliations

¹ Department of RNA Therapeutics, Merck & Co., Inc., West Point, PA 19486, USA.
² Department of RNA Therapeutics, Merck & Co., Inc., West Point, PA 19486, USA; Department of Infectious Diseases and Vaccines, Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: pedro.cejas@merck.com.

Abstract

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.

Keywords: RNAi; delivery; lung; siRNA.