Antisense Oligonucleotides Targeting Jagged 1 Reduce House Dust Mite-Induced Goblet Cell Metaplasia in the Adult Murine Lung.

Antisense Oligonucleotides Targeting Jagged 1 Reduce House Dust Mite-Induced Goblet Cell Metaplasia in the Adult Murine Lung. Am J Respir Cell Mol Biol. 2020 Mar 16;: Authors: Carrer M, Crosby JR, Sun G, Zhao C, Damle SS, Kuntz SG, Monia BP, Hart CE, Grossman TR Abstract Goblet cell metaplasia, excessive mucus production, and inadequate mucus clearance accompany and exacerbate multiple chronic respiratory disorders, such as asthma and COPD. Notch signaling plays a central role in controlling the fate of multiple cell types in the lung, including goblet cells. Here, we explored the therapeutic potential of modulating the Notch pathway in the adult murine lung using chemically-modified antisense oligonucleotides (ASOs). To this end, we designed and characterized ASOs targeting the Notch receptors Notch1, Notch2, and Notch3, and the Notch ligands Jag1 and Jag2. Pulmonary delivery of ASOs in healthy mice or mice exposed to house dust mite (HDM), a commonly utilized mouse model of asthma, resulted in the significant reduction of the respective mRNAs in the lung. Furthermore, ASO-mediated knockdown of Jag1 or Notch2 in the lung of healthy adult mice led to the downregulation of the club cell marker Scgb1a1, and the concomitant upregulation of the ciliated cell marker FoxJ1. Similarly, ASO-mediated knockdown of Jag1 or Notch2 in the HDM disease model led to reduced goblet cell metaplasia and decreased mucus production. Since goblet cell met...
Source: American Journal of Respiratory Cell and Molecular Biology - Category: Molecular Biology Authors: Tags: Am J Respir Cell Mol Biol Source Type: research