RNA Suppression Reverses the Cellular Cause of a Deadly Lung Disease

Pulmonary arterial hypertension (PAH) is a rare, chronic condition that thickens the walls of the pulmonary arteries, which carry blood from the heart to the lungs. As a result, the heart has to work extra hard to get blood around the body. Over time, the heart weakens and can eventually fail. Patients are in desperate need of treatments that address the disease’s underlying mechanisms.

Now, scientists have identified an RNA molecule critical to reshaping the key artery. In a new study published in Science Translational Medicine, they tweaked the levels of this RNA in mice.¹ This prevented the decline in heart function that is common in PAH. Despite being at an early stage, the findings could point the way to a new therapy for this rare and deadly condition.

Finding the Culprit in PAH

MicroRNAs are tiny, noncoding RNA molecules that control the expression of genes throughout the body. Researchers have long suspected they may play a role in PAH.

“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 vascular expert at Stanford University who wasn’t involved in the study, in a statement.

Previous studies reported that microRNA-224-5p (miR-224) was particularly upregulated in PAH patients’ lungs.² With this in mind, Yassine Sassi, a cardiopulmonary scientist at Virginia Tech who led the new study, explored whether shutting down miR-224 could help patients.

He and his team found that miR-224 regulated the production of pulmonary arterial smooth muscle cells in patients with PAH. Excessive numbers of these cells cause the thickening of the pulmonary arteries that kicks off PAH. The team showed that boosting miR-224 levels worsened symptoms in mice with an induced form of PAH. These results gave them confidence that they had identified a major culprit in the disease’s onset.

The team then suppressed miR-224. They used two techniques: In one, they released a nucleic acid construct called an antisense oligonucleotide that bound to miR-224 into the mice’s lungs. In another, they used an AAV1 gene therapy to shut down miR-224 in lung cells, achieving longer-term inhibition than the antisense oligonucleotide.

A True Disease-Modifying Therapy?

Whether they used a chemical or genetic method, miR-224 suppression had the desired effect, preventing remodeling of the mice’s arteries and preserving heart function. Sassi said that the success of their results in different models pointed to the integral role of miR-224 in PAH. “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,” he said.

De Jesus Perez added, “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.”