Lung-targeted delivery of TGF-β antisense oligonucleotides to treat pulmonary fibrosis

Junghyun Kim, Seulgi Jeon, Seong Jae Kang, Kyoung Ran Kim, Hien Bao Dieu Thai, Seokyung Lee, Sehoon Kim, Yun Sil Lee, Dae Ro Ahn

Research output: Contribution to journalArticle

Abstract

Pulmonary fibrosis is a serious respiratory disease, with limited therapeutic options. Since TGF-β is a critical factor in the fibrotic process, downregulation of this cytokine has been considered a potential approach for disease treatment. Herein, we designed a new lung-targeted delivery technology based on the complexation of polymeric antisense oligonucleotides (pASO) and dimeric human β-defensin 23 (DhBD23). Antisense oligonucleotides targeting TGF-β mRNA were polymerized by rolling circle amplification and complexed with DhBD23. After complexation with DhBD23, pASO showed improved serum stability and enhanced uptake by fibroblasts in vitro and lung-specific accumulation upon intravenous injection in vivo. The pASO/DhBD23 complex delivered into the lung downregulated target mRNA, and subsequently alleviated lung fibrosis in mice, as demonstrated by western blotting, quantitative reverse-transcriptase PCR (qRT-PCR), immunohistochemistry, and immunofluorescence imaging. Moreover, as the complex was prepared only with highly biocompatible materials such as DNA and human-derived peptides, no systemic toxicity was observed in major organs. Therefore, the pASO/DhBD23 complex is a promising gene therapy platform with lung-targeting ability to treat various pulmonary diseases, including pulmonary fibrosis, with low side effects.

Original languageEnglish
Pages (from-to)108-121
Number of pages14
JournalJournal of Controlled Release
Volume322
DOIs
Publication statusPublished - 2020 Jun 10
Externally publishedYes

Keywords

  • Human β-defensin
  • Polymeric antisense oligonucleotides
  • Pulmonary fibrosis
  • Rolling circle amplification

ASJC Scopus subject areas

  • Pharmaceutical Science

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  • Cite this

    Kim, J., Jeon, S., Kang, S. J., Kim, K. R., Thai, H. B. D., Lee, S., Kim, S., Lee, Y. S., & Ahn, D. R. (2020). Lung-targeted delivery of TGF-β antisense oligonucleotides to treat pulmonary fibrosis. Journal of Controlled Release, 322, 108-121. https://doi.org/10.1016/j.jconrel.2020.03.016