Blocking a naturally occurring molecule reverses deadly lung disease in preclinical models

Researchers blocked a naturally occurring molecule to reverse pulmonary arterial hypertension in preclinical models, a finding that could point to a new treatment approach for people with a rare and often fatal lung disease.

Pulmonary arterial hypertension, or PAH, damages the blood vessels in the lungs and makes it harder for the heart to pump blood. It affects the heart's right ventricle that supplies oxygen rich blood to the lungs and, if left untreated, can lead to heart failure and death within two to three years after diagnosis. 

In a study published in Science Translational Medicine and led by Yassine Sassi of the Fralin Biomedical Research Institute at VTC, researchers focused on microRNA-224, which was found at elevated levels in the lungs of patients with the disease and in patient-derived cells. 

The researchers found that higher levels of the molecule cause cells in the lung's blood vessels to grow and multiply in ways that worsen the disease. 

When the team blocked the molecule using two different approaches - a targeted drug-like therapy and a gene therapy technique - they reversed key signs of the disease in animal models, improving blood vessel function and heart performance and increasing survival in more severe cases. 

Unlike more standard gene therapies that replace faulty genes, this approach delivers genetic material into lung cells to block a signal that drives the disease. 

One of the most fascinating findings in this study is that this molecule can regulate several genes within a single pathway - one of the most important in this disease. We've been able to show that targeting this molecule can reverse the disease in multiple models, pointing to a new direction for developing treatments that address the underlying cause of the disease."

Yassine Sassi, study's senior author

Current treatments for pulmonary arterial hypertension are primarily palliative, focusing on easing symptoms and improving blood flow but do not cure the disease. The study found that the molecule disrupts a key balance inside cells that normally controls the thickening of blood vessel walls, and blocking it helps reverse the pathological process by restoring that balance. 

"Modern pulmonary hypertension therapeutics are increasingly shifting beyond vasodilatory agents toward disease-modifying strategies, and while microRNAs have long been attractive targets given their ability to regulate broad gene networks, identifying a disease-relevant and actionable candidate in PAH has remained a major challenge," said Vinicio de Jesus Perez, a professor of medicine at the Stanford School of Medicine, who was not involved in the research. 

"This is a strong and impactful study that identifies miR-224 as a central regulator of pulmonary vascular remodeling through coordinated suppression of BMP signaling and enhancement of TGF-beta driven proliferation, with compelling evidence that its inhibition reverses disease across multiple models and holds promise as a true disease-modifying therapy," de Jesus Perez said.

Researchers said more work is needed to determine whether targeting the molecule would be safe and effective in people.

The Science Translational Medicine study brought together researchers from multiple institutions in the United States, Europe, and Canada.

The research was supported by the National Institutes of Health, the American Heart Association, the American Lung Association and international cardiovascular research funding organizations.