Lung-targeted delivery of TGF-β antisense oligonucleotides to treat pulmonary fibrosis.
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| 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.
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| Authors | Junghyun Kim, Seulgi Jeon, Seong Jae Kang, Kyoung-Ran Kim, Hien Bao Dieu Thai, Seokyung Lee, Sehoon Kim, Yun-Sil Lee, Dae-Ro Ahn |
| Journal | Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 322 Pg. 108-121 (06 10 2020) ISSN: 1873-4995 [Electronic] Netherlands |
| PMID | 32179111 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2020 Elsevier B.V. All rights reserved. |
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