Blocking Epac1 Protein Slows Lung Fibrosis In Preclinical Models

Researchers astatine nan Icahn School of Medicine astatine Mount Sinai and collaborators person identified a antecedently overlooked protein, Epac1, arsenic a cardinal driver of idiopathic pulmonary fibrosis (IPF), a chronic and progressive lung-scarring disease. Their findings, demonstrated crossed compartment cultures, preclinical models, and samples of quality lung tissue, show that blocking Epac1 tin slow nan progression of nan disease.

Published successful nan July 7 online rumor of European Respiratory Journal [https://doi.org/10.1183/13993003.02250-2024], nan activity could pave nan measurement for a caller people of treatments to thief patients pinch this presently incurable condition.

IPF is simply a progressive, often fatal illness successful which lung insubstantial becomes thickened and scarred complete time, making it progressively difficult to breathe. With constricted curen options disposable today, researchers person been searching for caller ways to intervene earlier irreversible harm occurs.

We were motivated by nan urgent request for caller therapies. We focused connected Epac1 because we suspected this little-known macromolecule mightiness beryllium doing much harm than antecedently thought successful fibrotic lungs-and that turned retired to beryllium nan case."

Lahouaria Hadri, PhD, co-senior corresponding author, Associate Professor of Pharmacological Sciences, and Medicine (Cardiology), Icahn School of Medicine astatine Mount Sinai

Using lung insubstantial from IPF patients and patient individuals, arsenic good arsenic some cellular and rodent models, nan researchers recovered that Epac1 is importantly overactive successful fibrotic lungs. When they genetically removed Epac1 successful mice-or treated nan mice and quality lung insubstantial slices pinch a small-molecule supplier known arsenic AM-001, designed to inhibit nan protein-they observed a clear simplification successful lung scarring and fibrosis.

"This is nan first clip anyone has shown that Epac1 plays a harmful domiciled successful IPF and that targeting it pinch a supplier tin help," says Dr. Hadri "We were particularly encouraged to spot these protective effects crossed each models we tested-from cells to mice to quality lung tissue."

Importantly, nan study besides linked Epac1 activity to different biologic process known arsenic "neddylation," which is believed to beryllium progressive successful really proteins are regulated successful IPF. This find opens a caller avenue for knowing nan molecular underpinnings of nan disease, opportunity nan investigators.

While encouraging, nan researchers be aware that this is early-stage, preclinical research. They opportunity that overmuch much work, including testing successful larger animal models and eventual objective trials, is needed earlier Epac1 inhibitors for illustration AM-001 tin beryllium developed into a therapy for patients.

Still, they called nan findings an encouraging measurement toward nan improvement of targeted treatments that could slow aliases extremity nan progression of IPF, giving patients much clip and amended value of life. Next, nan squad plans to trial AM-001 successful much precocious models and research its effects connected different lung compartment types and molecular pathways.

"This investigation lays nan instauration for a wholly caller curen strategy," says Dr. Hadri. "If successful, it could make a existent quality for group pinch IPF, who presently person very fewer options."

The insubstantial is titled "Pharmacological Inhibition of Epac1 Protects against Pulmonary Fibrosis by Blocking FoxO3a Neddylation."

The study's authors, as listed successful nan 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.