Development and preclinical efficacy of novel transforming growth factor-β1 short interfering RNAs for pulmonary fibrosis.

Abstract

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.

• Authors: Corina N D'Alessandro-Gabazza, Tetsu Kobayashi, Daniel Boveda-Ruiz, Takehiro Takagi, Masaaki Toda, Paloma Gil-Bernabe, Yasushi Miyake, Atsushi Yasukawa, Yoshikazu Matsuda, Noboru Suzuki, Hiromitsu Saito, Yutaka Yano, Ayako Fukuda, Tetsuya Hasegawa, Hidekazu Toyobuku, Stephen I Rennard, Peter D Wagner, John Morser, Yoshiyuki Takei, Osamu Taguchi, Esteban C Gabazza
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 46 Issue 3 Pg. 397-406 (Mar 2012) ISSN: 1535-4989 [Electronic] United States
• PMID: 22033267 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aerosols
• RNA, Small Interfering
• TGFB1 protein, human
• Tgfb1 protein, mouse
• Transforming Growth Factor beta1
• Bleomycin

Topics

• Aerosols
• Animals
• Bleomycin
• Disease Models, Animal
• Female
• Gene Expression Regulation
• Genetic Therapy (methods)
• Humans
• Idiopathic Pulmonary Fibrosis (chemically induced, genetics, metabolism, pathology, physiopathology, therapy)
• Lung (metabolism, pathology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• RNA Interference
• RNA, Small Interfering (administration & dosage, metabolism)
• Time Factors
• Transforming Growth Factor beta1 (genetics, metabolism)