Home
|
Inbox
|
Search
|
View Abstract
SET9 Antisense Oligonucleotides Improved 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; }
A2328 - SET9 Antisense Oligonucleotides Improved Bleomycin Induced Pulmonary Fibrosis in Mice
Author Block: M. Zhang, J. R. Crosby, D. Bai, C. Zhao, B. P. Monia, S. Guo; Drug Discovery, Ionis Pharmaceuticals Inc, Carlsbad, CA, United States.
Rationale: Idiopathic Pulmonary Fibrosis (IPF) is a devastating fibrotic lung disease with ~40,000 Americans dying each year. Survival time from diagnosis of IPF is only 2-5 years. Currently available anti-fibrotic drugs for the treatment of IPF offer minimal improvement of lung function, while demonstrating common adverse effects and high drug discontinuation in patients. More effective and safer treatment opportunities for IPF patients are urgently needed. SET (Su(var)3-9, Enhancer-of-zeste and Trithorax) domain containing lysine methyltransferase 7 (SET9 or SET7/9) has been reported to play an important role in regulating pro-fibrogenic activity in IPF animal models through regulating TGFβ/SMAD7 signaling pathways. In addition, SET9 has been demonstrated to regulate expression of extracellular matrix (ECM) protein and epithelial-mesenchymal transition (EMT) genes. Methods: We designed and screened chemically modified SET9 antisense oligonucleotides (ASOs) that specifically inhibit SET9 expression in lung through orotracheal delivery in bleomycin induced IPF mice. mRNA expression levels of SET9 and fibrosis markers were measured by real time RT-PCR using Taqman probes. Collagen induction was assessed by Sirius Red staining in lung tissue. Lung function was measured by using a whole body plethysmograph (Buxco Electronics) to determine airway-hyperresponsiveness (AHR). Results: Top SET9 ASO leads achieved dose responsive SET9 mRNA target knockdown (≥70% at high dose) and improved bleomycin induced lung pathological changes: lung function and body weight loss were significantly improved and fibrosis markers (collagen1, SMA, CTGF and TIMP1) were reduced in the SET9 ASO treatment group compared with the control group. Conclusions: These findings demonstrate that a SET9 ASO approach may have therapeutic potential for IPF disease.
Author Block: M. Zhang, J. R. Crosby, D. Bai, C. Zhao, B. P. Monia, S. Guo; Drug Discovery, Ionis Pharmaceuticals Inc, Carlsbad, CA, United States.
Rationale: Idiopathic Pulmonary Fibrosis (IPF) is a devastating fibrotic lung disease with ~40,000 Americans dying each year. Survival time from diagnosis of IPF is only 2-5 years. Currently available anti-fibrotic drugs for the treatment of IPF offer minimal improvement of lung function, while demonstrating common adverse effects and high drug discontinuation in patients. More effective and safer treatment opportunities for IPF patients are urgently needed. SET (Su(var)3-9, Enhancer-of-zeste and Trithorax) domain containing lysine methyltransferase 7 (SET9 or SET7/9) has been reported to play an important role in regulating pro-fibrogenic activity in IPF animal models through regulating TGFβ/SMAD7 signaling pathways. In addition, SET9 has been demonstrated to regulate expression of extracellular matrix (ECM) protein and epithelial-mesenchymal transition (EMT) genes. Methods: We designed and screened chemically modified SET9 antisense oligonucleotides (ASOs) that specifically inhibit SET9 expression in lung through orotracheal delivery in bleomycin induced IPF mice. mRNA expression levels of SET9 and fibrosis markers were measured by real time RT-PCR using Taqman probes. Collagen induction was assessed by Sirius Red staining in lung tissue. Lung function was measured by using a whole body plethysmograph (Buxco Electronics) to determine airway-hyperresponsiveness (AHR). Results: Top SET9 ASO leads achieved dose responsive SET9 mRNA target knockdown (≥70% at high dose) and improved bleomycin induced lung pathological changes: lung function and body weight loss were significantly improved and fibrosis markers (collagen1, SMA, CTGF and TIMP1) were reduced in the SET9 ASO treatment group compared with the control group. Conclusions: These findings demonstrate that a SET9 ASO approach may have therapeutic potential for IPF disease.
|
Home
|
Inbox
|
Search
|