Development and Preclinical Efficacy of Novel Transforming Growth Factor-β1 Short Interfering RNAs for Pulmonary Fibrosis
| Autor: | Peter D. Wagner, Masaaki Toda, Tetsu Kobayashi, Ayako Fukuda, Yutaka Yano, Esteban C. Gabazza, Takehiro Takagi, Osamu Taguchi, Stephen I. Rennard, Tetsuya Hasegawa, John Morser, Paloma Gil-Bernabe, Hidekazu Toyobuku, Yasushi Miyake, Corina N. D’Alessandro-Gabazza, Yoshiyuki Takei, Daniel Boveda-Ruiz, Noboru Suzuki, Hiromitsu Saito, Atsushi Yasukawa, Yoshikazu Matsuda |
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| Rok vydání: | 2012 |
| Předmět: |
Pulmonary and Respiratory Medicine
Small interfering RNA Time Factors Transgene Clinical Biochemistry Mice Transgenic Bleomycin Transforming Growth Factor beta1 Pathogenesis Mice chemistry.chemical_compound Idiopathic pulmonary fibrosis RNA interference Pulmonary fibrosis medicine Animals Humans RNA Small Interfering Lung Molecular Biology Aerosols business.industry Genetic Therapy Cell Biology medicine.disease Idiopathic Pulmonary Fibrosis Mice Inbred C57BL Disease Models Animal Gene Expression Regulation chemistry Immunology Female RNA Interference business Transforming growth factor |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 46:397-406 |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2011-0158oc |
| Popis: | Idiopathic pulmonary fibrosis is a chronic devastating disease of unknown etiology. No therapy is currently available. A growing body of evidence supports the role of transforming growth factor (TGF)-β1 as the major player in the pathogenesis of the disease. However, attempts to control its expression and to improve the outcome of pulmonary fibrosis have been disappointing. We tested the hypothesis that TGF-β1 is the dominant factor in the acute and chronic phases of pulmonary fibrosis and developed short interfering (si)RNAs directed toward molecules implicated in the disease. This study developed novel sequences of siRNAs targeting the TGF-β1 gene and evaluated their therapeutic efficacy in two models of pulmonary fibrosis: a model induced by bleomycin and a novel model of the disease developed spontaneously in mice overexpressing the full length of human TGF-β1 in the lungs. Intrapulmonary delivery of aerosolized siRNAs of TGF-β1 with sequences common to humans and rodents significantly inhibited bleomycin-induced pulmonary fibrosis in the acute and chronic phases of the disease and in a dose-dependent manner. Aerosolized human-specific siRNA also efficiently inhibited pulmonary fibrosis, improved lung function, and prolonged survival in human TGF-β1 transgenic mice. Mice showed no off-target effects after intratracheal administration of siRNA. These results suggest the applicability of these novel siRNAs as tools for treating pulmonary fibrosis in humans. |
| Databáze: | OpenAIRE |
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