Researchers at the Icahn School of Medicine at Mount Sinai and collaborators have identified a previously overlooked protein, Epac1, as a key driver of idiopathic pulmonary fibrosis (IPF), a chronic and progressive lung-scarring disease. Their findings, demonstrated across cell cultures, preclinical models, and samples of human lung tissue, show that blocking Epac1 can slow the progression of the disease.
Published in the July 7 online issue of European Respiratory Journal [ https://doi.org/10.1183/13993003.02250-2024 ], the work could pave the way for a new class of treatments to help patients with this currently incurable condition.
IPF is a progressive, often fatal disease in which lung tissue becomes thickened and scarred over time, making it increasingly difficult to breathe. With limited treatment options available today, researchers have been searching for new ways to intervene before irreversible damage occurs.
"We were motivated by the urgent need for new therapies," says co-senior corresponding author Lahouaria Hadri, PhD , Associate Professor of Pharmacological Sciences, and Medicine (Cardiology), at the Icahn School of Medicine at Mount Sinai. "We focused on Epac1 because we suspected this little-known protein might be doing more harm than previously thought in fibrotic lungs—and that turned out to be the case."
Using lung tissue from IPF patients and healthy individuals, as well as both cellular and mouse models, the researchers found that Epac1 is significantly overactive in fibrotic lungs. When they genetically removed Epac1 in mice—or treated the mice and human lung tissue slices with a small-molecule drug known as AM-001, designed to inhibit the protein—they observed a clear reduction in lung scarring and fibrosis.
"This is the first time anyone has shown that Epac1 plays a harmful role in IPF and that targeting it with a drug can help," says Dr. Hadri "We were especially encouraged to see these protective effects across all models we tested—from cells to mice to human lung tissue."
Importantly, the study also linked Epac1 activity to another biological process known as "neddylation," which is believed to be involved in how proteins are regulated in IPF. This discovery opens a new avenue for understanding the molecular underpinnings of the disease, say the investigators.
While encouraging, the researchers caution that this is early-stage, preclinical research. They say that much more work, including testing in larger animal models and eventual clinical trials, is needed before Epac1 inhibitors like AM-001 can be developed into a therapy for patients.
Still, they called the findings an encouraging step toward the development of targeted treatments that could slow or stop the progression of IPF, giving patients more time and better quality of life. Next, the team plans to test AM-001 in more advanced models and explore its effects on other lung cell types and molecular pathways.
"This research lays the foundation for a completely new treatment strategy," says Dr. Hadri. "If successful, it could make a real difference for people with IPF, who currently have very few options."
The paper is titled "Pharmacological Inhibition of Epac1 Protects against Pulmonary Fibrosis by Blocking FoxO3a Neddylation."
The study's authors, as listed in the journal, are Katherine Jankowski, Sarah E. Lemay, Daniel Lozano-ojalvo, Leticia Perez-Rodriguez, Mélanie Sauvaget, Sandra Breuils-Bonnet, Karina Formoso, Vineeta Jagana, Maria T. Ochoa, Shihong Zhang, Javier Milara, Julio Cortijo, Irene C. Turnbull, Steeve Provencher, Sebastien Bonnet, Jordi Ochando, Frank Lezoualc'h, Malik Bisserier and Lahouaria Hadri.
See the journal paper for details on funding and conflicts of interest: [ https://doi.org/10.1183/13993003.02250-2024 ].
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City's large and diverse patient population.
The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master's degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,600 clinical residents and fellows training throughout the Health System. Its Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 560 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges. More than 4,500 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai
