Fig. 9
Antisense oligonucleotide silencing of FUS is a novel therapeutic intervention for IPF. Schematic representation of this study showing two cell types, fibroblasts and epithelial cells, under three different conditions: a healthy, b IPF, and c IPF PCLs/cells treated with FUS-ASO or ION363. As depicted, normal levels of FUS protein in the nucleus and healthy nucleus-cytoplasmic shuttling of FUS (solid arrows), accompanied by healthy inflammation, regulated cytokine profiles and active epithelial cell homeostasis, are natural phenomena in healthy cells (a). Under IPF conditions, FUS accumulates in the nucleus and more so in the cytoplasm along with its profibrotic client RNAs, which may alter their metabolism. This results in the upregulation of profibrotic gene signatures, namely, collagens, TGFB, IL11 and other genes of the ECM in fibroblasts. On the other hand, the already injured epithelium (respiratory/alveolar) shows activation of cytokeratins (KRT5 & 14) and aberrant surfactant homeostasis (b). In response to ION363 treatment, the protein levels of FUS are decreased in fibroblasts, leading to a downregulation of its profibrotic, client RNAs, as depicted. In epithelial cells, SFTPA1/2, ABCA3, NAPSA, and LAMP3 are upregulated, whereas MUC5B/5AC, KRT5, and KRT14 are downregulated, indicating decreased profibrotic signaling (c). The fibroblast- and epithelial-specific genes among the top 50 DEGs from our RNA-seq analysis are depicted here for a simplified understanding. d A consolidated summary: Silencing of FUS in IPF lungs via an antisense oligonucleotide, ION373, restores homeostasis by suppressing fibrotic transcriptional programs (by remodeling the ECM and reducing fibroblast proliferation) and promoting repair processes (alveolar repair and regeneration), supporting its candidacy as a novel therapeutic target in IPF
