Team’s work represents the first demonstration that pulmonary fibrosis may be reversed
The Advancements in Innovative Respiratory Research (AIR) translational team of the Institute for Clinical and Translational Research has been awarded a four-year, $3.1 million Technology/Therapeutic Development Award from the Department of War’s Congressionally Directed Medical Research Programs (award #HT9425261E418) to advance a novel treatment for idiopathic pulmonary fibrosis (IPF).
IPF is a progressive, ultimately fatal scarring disease of the lungs with no cure. Rates of the disease are rising among U.S. veterans, particularly those exposed to burn pits and other respiratory toxicants during deployment in combat zones.
The award brings together a multi-institutional team that combines expertise in molecular immunology, pulmonary medicine, and medicinal chemistry, including:
- Allan Brasier, MD, project lead
- Nathan Sandbo, MD, Professor in the Department of Medicine and expert in lung mesenchyme
- Jeremy Katzen, MD, of the University of Pennsylvania, a physician-scientist with expertise in epithelial cell stress in interstitial lung disease, and
- Jia Zhou, PhD, medicinal chemist at the University of Texas Medical Branch.
Brasier and colleagues discovered an epigenetic regulator that drives stress responses in lung epithelial cells, fueling the expansion of scar-forming myofibroblasts and the disorganized extracellular matrix (ECM) deposition characteristic of IPF.
Building on this discovery, the team designed and validated ZL0969, a highly selective BRD4 inhibitor with favorable drug-like properties — including high oral bioavailability, a long half-life, and no detectable toxicity in preclinical studies.
In therapeutic trials using bleomycin-challenged mouse models, daily administration of ZL0969 reduced populations of fibrosing fibroblasts and dystrophic epithelium, blocked disorganized ECM deposition, and significantly improved survival. According to the research team, this represents the first demonstration that pulmonary fibrosis can be reversed by targeting an epigenetic regulator — a potential paradigm shift in IPF treatment.
The new funding will support a milestone-driven program to establish ZL0969’s therapeutic efficacy, solidify its safety profile, and build the regulatory package needed for Investigational New Drug (IND) approval.
By advancing a first-in-class epigenetic therapy toward clinical testing, the AIR team aims to bring a new treatment option to veterans and other patients facing this devastating diagnosis — one for which current therapies can slow, but not reverse, disease progression.
At the Institute for Clinical and Translational Research, Brasier serves as Co-Executive Director and leads its nationally recognized Team Science Program. The evidence-based infrastructure underlying team science has been highly valuable for Brasier and his colleagues working on IPF research.
“A team approach is essential for advancing therapies for complex human diseases,” said Brasier. “This advance was made possible by an inter-institutional collaboration between medicinal chemists, epithelial biologists, translational researchers and pulmonary disease specialists. New and exciting frontiers are being advanced in clinical applications focusing on real-time disease monitoring and artificial intelligence/machine learning for more accurate diagnoses.”