UIC scientists develop promising therapy for deadly lung condition

Researchers at the University of Illinois Chicago have developed a drug-like molecule that can restore function in the lungs of people experiencing acute respiratory distress syndrome, a severe condition that can lead to respiratory failure and death. The therapy, which has been tested in mice, stops fluid from leaking out of lungs' blood vessels and improves lung function, the scientists report in the Nature portfolio journal Signal Transduction and Targeted Therapy.

"We can effectively treat patients who already experience or develop respiratory distress syndrome," said Yulia Komarova, professor of pharmacology and regenerative medicine in the University of Illinois College of Medicine, who led the study. "It's very stable, very safe," Komarova said of the treatment.

Acute respiratory distress syndrome can arise from many causes, including pneumonia, sepsis and COVID-19. Regardless of cause, the condition is marked by leakage from blood vessels that leads to pathological changes in the lung, Komarova said. Fluid builds up in the lungs, and lung failure can follow, proving disastrous if not fatal for the rest of the body.

"Once the function of this vital organ is disturbed, the entire body starts suffering," Komarova said. The mortality rate of the condition is between 40% and 60%, depending on the patient's age and clinical history, and there are no therapies currently on the market to treat it. Patients are typically given oxygen support and put on a mechanical ventilator, which is invasive and can damage the lungs by applying unnatural, non-uniform pressure.

"This is still an area of urgent unmet need," Komarova said.

In previous research, Komarova and her lab found that a protein called EB3 turns on calcium signals in blood vessel cells that trigger this leakage. In the new study, they created a molecule that inhibits the EB3 protein's function and named it VT-109. They then tested VT-109's effects on acute respiratory distress syndrome, evaluating its performance on multiple causes of the disease. These included sepsis, hospital-acquired pneumonia, SARS-CoV-2 and endotoxemia, or the presence of endotoxins in the blood.

Across this array of causes, treating sick mice with VT-109 improved lung function, restoring the balance of fluid in the lungs and improving their ability to expand, also called compliance.

"One dose of the drug in mice in 24 hours completely restores lung compliance to its normal healthy baseline," Komarova said.

Treatment with VT-109 also reined in immune cells like neutrophils, which infiltrate damaged lungs and lead to inflammation.

"Regardless of the cause, if we treat vascular leakage, we can also reduce recruitment of neutrophils into the lung tissue, significantly diminishing damage and actually helping the lung to regenerate and restore not only its function but also its architecture," Komarova said.

What's more, VT-109 had a broad therapeutic window, she said. The researchers tested the treatment both early and late in the onset of acute respiratory distress syndrome and saw its positive effects in both cases. In further experiments, Komarova and her colleagues found that VT-109 activates a cellular factor called FOXM1, which in turn kicks off the regeneration and repair effects that help heal the diseased lungs. After further tests of the drug's safety, Komarova and UIC researchers will partner with clinicians at Oregon Health Sciences University for clinical trials.

The study's first authors are Wan Ching Chan, Man Long Kwok and Xinyan Qu. Co-authors of the study include Hazem Abdelkarim, Jonathan Le, Deying Yang, Avik Banerjee, Shuangping Zhao, Jacob Class, Marlen Gonzalea, Harry Hailemeskel, Raman Ghotra Singh, Mark Maienschein-Cline, Matthew Lindeblad, Kasim Kabirov, Alex Lyubimov, Batrick Belvitch, Justin Richner and Vadim Gaponenko of UIC, and Ricardo Gallardo-Macias and Vadim J. Gurvich of the University of Minnesota.