Scientists have harnessed the power of genomic big data and animal models of to identify the underlying causes and potential new treatments for idiopathic pulmonary fibrosis (IPF), a lung disease that kills an estimated 40,000 people annually in the United States.
IPF is a chronic and ultimately fatal disease in which tissue deep in the lungs becomes increasingly thick and stiff, or scarred, over time, making breathing more and more difficult. A research team at Cincinnati Children’s Hospital Medical Center found that in IPF patients, the activity of a particular protein, Hsp90 (Heat shock protein 90), is elevated in fibroblasts. Fibroblasts are cells in connective tissues that produce collagen and other fibers that have not yet progressed to form scar tissue.
They also identified Hsp90 inhibitors as a potentially effective therapy to stop fibroblast activation in IPF.
The research team was led by Anil Goud Jegga, DVM, of the Division of Biomedical Informatics and Satish K. Madala, PhD, of the Division of Pulmonary Medicine. The paper was published this week in the journal JCI Insight.
“We investigated how fibroblasts become dysregulated, leading to their persistent activation and fibrosis,” says Jegga. “We found that Hsp90 activity is elevated in fibroblasts isolated from fibrotic lesions and that it serves to activate the development of pulmonary fibrosis. By understanding this molecular mechanism, we were able to identify and test a potential treatment to reverse established and ongoing fibrotic lung disease.”
In the study, the investigators integrated publicly available gene expression data from IPF patients, transcriptional signatures from small molecule pertubagens (substances designed to disruptintracellular processes), and systems biology-based approaches to better understand the underlying biology of the disorder.
The team also identified candidate treatments that attenuated the progression of established fibrotic lung disease. In particular, 17-AAG (17-N-allylamino-17-demethoxygeldanamycin or tanespimycin), a potent inhibitor of Hsp90 activity, was shown to attenuate Hsp90-driven fibroblast activation. They found that in vivo therapy with 17-AAG significantly attenuated progression of established and ongoing fibrosis in a mouse model of lung fibrosis.
“Our study also provides preclinical data to test safety and efficacy of 17-AAG or other Hsp90 inhibitors as potential treatment in patients with severe fibrotic lung disease,” says Madala. “The small molecule Hsp90 inhibitors are currently in advanced clinical trials for various cancers. Hence, findings of this study can be relatively rapidly translated into clinical trials in patients with fibrotic diseases.”
Since the current project was conducted in mouse models and human cells derived from lung biopsies of IPF patients, Madala and Jegga stress that additional studies are needed before determining whether targeting Hsp90 would be effective and safe enough to test in human patients.