Targeting murine alveolar macrophages by the intratracheal administration of locked nucleic acid containing antisense oligonucleotides

Drug Delivery
Yasunori Uemura, Katsuya Kobayashi

Abstract

The pulmonary delivery of locked nucleic acid containing antisense oligonucleotides (LNA-ASOs) is expected to be a novel therapeutic approach for lung diseases. However, there are two concerns to be considered: immune responses, as the lung has a distinct immune mechanism to protect it from inhaled pathogens; and leakage into blood, since the lung is permeable to small molecules. As phagocytic alveolar macrophages reside in the alveolar space, it is hypothesized that inhaled LNA-ASOs effectively accumulate and exert a knockdown (KD) effect on these cells at low doses. Thus, targeting alveolar macrophages by inhaled LNA-ASOs may reduce these risks. To test this hypothesis, LNA-ASOs targeting Scarb1 or Hprt1 were intratracheally administered to mice. We confirmed the remarkable accumulation of intratracheally administered LNA-ASOs in murine alveolar macrophages and found that they exerted a significant and sequence-dependent KD effect. The dose required for KD in alveolar macrophages was lower than that required to induce KD in the whole lung. Furthermore, when a KD effect was observed in alveolar macrophages, no KD effect was observed in the liver or kidney; however, several inflammatory cytokines were increased in the lung. The...Continue Reading

References

Aug 23, 2005·Proceedings of the American Thoracic Society·John S PattonJeffry G Weers
Apr 9, 2008·Nanomedicine·Reiner Peters
Feb 20, 2010·American Journal of Respiratory and Critical Care Medicine·Bastian OpitzNorbert Suttorp
Mar 17, 2010·Chemistry & Biodiversity·Rakesh N Veedu, Jesper Wengel
Nov 27, 2010·Journal of Inflammation·Erin I LaffertyMarkus Schnare
Jan 22, 2014·Nature Reviews. Immunology·Tracy Hussell, Thomas J Bell
Oct 1, 2005·Drug Discovery Today. Technologies·Sakari KauppinenJesper Wengel
Dec 19, 2014·Nature Immunology·Manfred KopfSamuel P Nobs
Feb 24, 2015·Immunological Reviews·Günter Weiss, Ulrich E Schaible
Sep 2, 2015·European Respiratory Review : an Official Journal of the European Respiratory Society·Luisa Morales-NebredaG R Scott Budinger
Jul 3, 2016·Journal of Controlled Release : Official Journal of the Controlled Release Society·Tsukasa SugoHirokazu Matsumoto
Mar 1, 2017·Nature Biotechnology·Stanley T CrookeXue-Hai Liang
Apr 6, 2017·Cardiology in Review·Jason Chan, Angela Cheng-Lai
Oct 11, 2017·Drug Discovery Today·Peter H HagedornTroels Koch
Dec 15, 2017·Nucleic Acids Research·Xiulong Shen, David R Corey
Apr 25, 2018·Pharmaceutical Development and Technology·Yasunori UemuraKatsuya Kobayashi
Jun 21, 2018·International Journal of Molecular Sciences·Chiraz AtriDhafer Laouini
Jan 30, 2019·Annual Review of Medicine·C Frank Bennett

❮ Previous
Next ❯

Citations


❮ Previous
Next ❯

Methods Mentioned

BETA
flow cytometry
FACS
bronchoalveolar lavage
transfection

Software Mentioned

SAS
gentleMACS Dissociator
Treestar
FlowJo

Related Concepts

Related Feeds

Antisense Oligonucleotides: ND

This feed focuses on antisense oligonucleotide therapies such as Inotersen, Nusinursen, and Patisiran, in neurodegenerative diseases including amyotrophic lateral sclerosis.

Cancer Vaccines

Cancer vaccines are vaccines that either treat existing cancer or prevent development of a cancer.