Home
|
Inbox
|
Search
|
View Abstract
NOX4 Antisense Oligonucleotides Are Effective at Preventing Bleomycin-Induced Pulmonary Fibrosis in Mice
Description
.abstract img { width:300px !important; height:auto; display:block; text-align:center; margin-top:10px } .abstract { overflow-x:scroll } .abstract table { width:100%; display:block; border:hidden; border-collapse: collapse; margin-top:10px } .abstract td, th { border-top: 1px solid #ddd; padding: 4px 8px; } .abstract tbody tr:nth-child(even) td { background-color: #efefef; } .abstract a { overflow-wrap: break-word; word-wrap: break-word; }
A2362 - NOX4 Antisense Oligonucleotides Are Effective at Preventing Bleomycin-Induced Pulmonary Fibrosis in Mice
Author Block: C. Zhao, J. R. Crosby, D. Bai, M. Zhang, A. Bell, B. Monia, S. Guo; Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, CA, United States.
RATIONALE: Pulmonary fibrosis (PF) is a respiratory disease which leads to the deposition of excessive extracellular matrix. For most patients there is no diagnosed cause or effective therapy available. NADPH oxidase 4 (NOX4) is upregulated in fibroblasts from IPF patients and has been demonstrated to modulate the conversion of fibroblasts into myofibroblasts. In addition, apoptosis of alveolar epithelial cells observed in the bleomycin model was abrogated in NOX4-deficient mice and fibrosis was reduced. We have evaluated a NOX4 antisense strategy for the treatment of pulmonary fibrosis.
METHODS: Previously, we have found that inhaled antisense oligonucleotides (ASOs) distribute broadly into many cell types in the lung where they downregulate gene expression by inducing RNase H dependent degradation of targeted mRNAs. To test the ability of ASOs to distribute throughout a fibrotic lung, ASOs targeting a ubiquitously expressed protein were administered by aerosol to mice both before and after bleomycin–induced pulmonary fibrosis was established. To test NOX4 as a target for pulmonary fibrosis, NOX4 ASOs were administered to the lungs of mice twice a week throughout the study with orotracheally administered bleomycin given 2 weeks after ASO treatment initiation and endpoints collected at both 7 and 21 days after Bleomycin instillation.
RESULTS: Immunohistochemistry specific for ASOs demonstrated the ability for ASOs to target the majority of lung cell types in both normal and fibrotic regions. NOX4 ASOs potently reduced target mRNA in lung, minimized body weight loss and improved survival. In addition, neutrophil recruitment to the BAL, lung function, and lung fibrosis, both mRNA for fibrosis markers (including collagen) and Sirius Red stain, were all reduced with NOX4 ASO compared to a control ASO.
CONCLUSIONS: The ability to target any gene in the lung with minimal systemic exposure demonstrates that antisense therapy may provide a novel, potent and safe treatment for pulmonary fibrosis and that targeting NOX4 has therapeutic potential for PF disease.
Author Block: C. Zhao, J. R. Crosby, D. Bai, M. Zhang, A. Bell, B. Monia, S. Guo; Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, CA, United States.
RATIONALE: Pulmonary fibrosis (PF) is a respiratory disease which leads to the deposition of excessive extracellular matrix. For most patients there is no diagnosed cause or effective therapy available. NADPH oxidase 4 (NOX4) is upregulated in fibroblasts from IPF patients and has been demonstrated to modulate the conversion of fibroblasts into myofibroblasts. In addition, apoptosis of alveolar epithelial cells observed in the bleomycin model was abrogated in NOX4-deficient mice and fibrosis was reduced. We have evaluated a NOX4 antisense strategy for the treatment of pulmonary fibrosis.
METHODS: Previously, we have found that inhaled antisense oligonucleotides (ASOs) distribute broadly into many cell types in the lung where they downregulate gene expression by inducing RNase H dependent degradation of targeted mRNAs. To test the ability of ASOs to distribute throughout a fibrotic lung, ASOs targeting a ubiquitously expressed protein were administered by aerosol to mice both before and after bleomycin–induced pulmonary fibrosis was established. To test NOX4 as a target for pulmonary fibrosis, NOX4 ASOs were administered to the lungs of mice twice a week throughout the study with orotracheally administered bleomycin given 2 weeks after ASO treatment initiation and endpoints collected at both 7 and 21 days after Bleomycin instillation.
RESULTS: Immunohistochemistry specific for ASOs demonstrated the ability for ASOs to target the majority of lung cell types in both normal and fibrotic regions. NOX4 ASOs potently reduced target mRNA in lung, minimized body weight loss and improved survival. In addition, neutrophil recruitment to the BAL, lung function, and lung fibrosis, both mRNA for fibrosis markers (including collagen) and Sirius Red stain, were all reduced with NOX4 ASO compared to a control ASO.
CONCLUSIONS: The ability to target any gene in the lung with minimal systemic exposure demonstrates that antisense therapy may provide a novel, potent and safe treatment for pulmonary fibrosis and that targeting NOX4 has therapeutic potential for PF disease.
|
Home
|
Inbox
|
Search
|