Ofev Affects Cell Cycle Genes in IPF Fibroblasts, Study Finds

Ofev (nintedanib) may exert its therapeutic benefits by halting the activity of genes that promote proliferation of fibroblasts in idiopathic pulmonary fibrosis (IPF), a next-generation sequencing study suggests.

The study “Gene Expression Changes Associated with Nintedanib Treatment in Idiopathic Pulmonary Fibrosis Fibroblasts: A Next-Generation Sequencing and Bioinformatics Study” was published in the Journal of Clinical Medicine.

In IPF, cells from the lung epithelium are activated and produce signals that promote fibrosis (scarring), and the proliferation of fibroblasts and myofibroblasts (the cells responsible for fibrosis). Once activated, these cells secrete an excess of extracellular proteins (like collagen) that form scars and destroy the lung tissue.

Currently, only two agents have demonstrated effectiveness against IPF:  Boehringer Ingelheim’s Ofev and Genentech’s Esbriet (pirfenidone). Ofev, a tyrosine kinase inhibitor that targets many receptors expressed in fibroblasts cells, was approved  as an IPF treatment in 2014 by the U.S. Food and Drug Administration (FDA), and in Europe in 2015.

The main targets of Ofev are the fibroblast growth factor receptor (FGFR), vascular endothelial growth receptor (VEFGR), and platelet-derived growth factor receptor (PDGFR). Ofev competes with the natural ligands of these receptors by blocking them, and consequently compromising the proliferation, migration, and activation of fibroblasts.

A research team from the Kaohsiung Medical University Hospital, in Taiwan, aimed to understand how Ofev affects gene levels in IPF fibroblasts. According to the team, how Ofev “changes gene regulation in IPF has never been systematically investigated.”

The team tested different concentrations of Ofev in human IPF lung fibroblasts.

Results showed that at two concentrations — 2 and 4 micromolars — Ofev led to significant cell growth inhibition and cell autophagy (a process to eliminate damaged molecules, organelles, or cells).

Researchers then conducted a next-generation sequencing analysis of fibroblasts treated with the two concentrations of Ofev, and compared the results to untreated fibroblasts. The team focused on the therapy’s effects in messenger RNA (the molecule transcribed from DNA and important for protein production) and microRNA profile (microRNAs are a special class of short RNA molecules capable of regulating gene expression).

From the RNA screening, the team selected genes that were deregulated compared to controls in a dose dependent-manner. In total, the levels of 157 genes were increased, and that of 151 genes were reduced.

A bioinformatic analysis showed that the top deregulated genes in IPF fibroblasts were involved in cell division, nuclear division, and processes related with DNA replication that occur before cell division. Moreover, researchers identified a microRNA — called hsa-miR-486-3p — that inhibited the expression of specific genes (namely DDX11, E2F1, and PLXNA4) linked to cell proliferation, migration, and regulation of the cell cycle and cell death.

“In IPF, we found nintedanib [Ofev] treatment was associated with up-regulation of hsa-miR-486-3p, which might repress DDX11, E2F1, and PLXNA4 expressions. These together might contribute to decreased proliferation of fibroblasts,” researchers wrote.

Overall, the results support the anti-fibrotic action of Ofev, and suggest how it effects fibroblasts at a genetic level by deregulating cell proliferation associated-genes.

“Our findings improve current understandings of molecular mechanisms of nintedanib treatment in IPF,” the team concluded. Further studies are needed, however, to confirm the results.