Development and preclinical efficacy of novel transforming growth factor-β1 short interfering RNAs for pulmonary fibrosis.
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.
Department of Immunology, Mie University School of Medicine, Edobashi 2-174, Tsu city, Mie prefecture 514 8507, Japan. gabazza@doc.medic.mie-u.ac.jp
Corina N
CN
D'Alessandro-Gabazza
Tetsu
T
Kobayashi
Daniel
D
Boveda-Ruiz
Takehiro
T
Takagi
Masaaki
M
Toda
Paloma
P
Gil-Bernabe
Yasushi
Y
Miyake
Atsushi
A
Yasukawa
Yoshikazu
Y
Matsuda
Noboru
N
Suzuki
Hiromitsu
H
Saito
Yutaka
Y
Yano
Ayako
A
Fukuda
Tetsuya
T
Hasegawa
Hidekazu
H
Toyobuku
Stephen I
SI
Rennard
Peter D
PD
Wagner
John
J
Morser
Yoshiyuki
Y
Takei
Osamu
O
Taguchi
Esteban C
EC
Gabazza
D000336:Aerosols; D000818:Animals; D001761:Bleomycin; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000378:metabolism*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
D000336:Aerosols; D034741:RNA, Small Interfering; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D001761:Bleomycin