Transcriptomics-based Screening of Repurposing Drug for Idiopathic Pulmonary Fibrosis

IPF is a pathological condition resulting from injury to the lungs and an ensuing fibrotic response leading to thickening of the alveolar walls and the obliteration of the alveolar space. The etiology of IPF and the role of the microenvironment in disease progression are largely unknown. We first used the repurposing pipeline to explore disease biology for the identification of relevant cell populations and then applied the screening pipeline to discover novel compounds. Using various types of RNAseq data from multiple datasets, we constructed signatures that capture different aspects of IPF biology, such as those related to cell type-specific transcriptional changes and those associated with disease development in animal models. We predicted and tested drugs targeting various IPF signatures and identified Pyrithyldione as our top candidate for reduction of fibrosis in the human precision-cut lung slices PCLS model and RNAseq was conducted on treated and untreated paired adjacent patient samples to determine its the effects on gene expression. Overall design: IPF lung explant samples were obtained from 6 patients, undergoing lung transplantation at Richard Devos Heart and Lung Transplantation Center, Corewell Health Butterworth Hospital, Grand Rapids, Michigan. Pathologic assessment confirmed the findings of advanced usual interstitial pneumonia (UIP) in the IPF subjects. All protocols were performed in compliance with relevant ethical regulations approved by local Institutional Review Board (IRB #: CHW 2017-198); Written informed consent was obtained from all patients who participated in the current study. Differential gene expression analysis of RNA-seq data for IPF Patients was performed between samples treated with a. Pyrithyldione or b. DMSO.