Study identifies potential immune targets for PAH therapy

Inhibiting activity of the ROCK2 gene, among others, merits further study

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Immune-related genes that could serve as potential therapeutic targets for pulmonary arterial hypertension (PAH) were identified in a recent study.

Among them was ROCK2, which was found to have increased gene activity in PAH patients’ lung tissue and animal models. Therapeutic molecules to inhibit the ROCK2 protein are already being tested for other diseases, and could show promise for PAH.

“Further in vivo [in live animals] data and clinical trials are warranted to investigate the role of inflammation and immune [signaling] in PAH progression,” the researchers wrote.

The study, “Identification of immune-associated signatures and potential therapeutic targets for pulmonary arterial hypertension,” was published in the Journal of Cellular and Molecular Medicine.

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PAH, characterized by a narrowing of the vessels carrying blood from the heart to the lungs, has many possible causes, including heart abnormalities, viral infections, connective tissue disorders, and certain medications.

Dysregulated immune signaling and inflammation are found to be common between all of them. It now is recognized that inflammation may contribute to pulmonary vascular remodeling, the disease-driving process in which structural changes to blood vessels leads to their narrowing.

That has paved the way for novel treatment approaches targeting inflammatory molecules and cells implicated in PAH. Still, to develop better treatments, a deeper understanding of immune mechanisms in the disease is warranted, according to scientists.

In their study, the team searched for immune signatures that might be associated with the disease, and possibly be new treatment targets.

They examined gene activity, or expression, data from the lung tissue of 96 PAH patients and 49 people without PAH, who served as a control group, which were housed across three different datasets.

Many gene activity levels related to inflammation, hypoxia

Overall, 475 genes had significantly different expression levels in PAH compared to controls, many of which were related to inflammation and responses to hypoxia, or low oxygen.

Gene expression profiles also could be used to estimate whether the abundance of different immune cell types in the lung tissue was altered. Of 22 immune cell types that did differ between the groups, CD4-positive T-cells were able to distinguish PAH best.

CD4-positive cells encompass different T-cell subsets, including both pro- and anti-inflammatory ones. Naïve T-cells, or those not yet primed to launch an immune attack against a target, were seen at lower levels in PAH tissue, whereas activated ones and ones primed for an immune attack were elevated.

The scientists also identified six so-called hub genes that formed a core immune-related gene signature in PAH. These six genes together — IL-2rb, ROCK2, ATHL1, CD52, HSP90AA1 and ACTR2 — could distinguish PAH tissue with more than 90% accuracy.

In both rat and mouse PAH models, four of these hub genes were found to have increased expression compared to healthy rats, including ROCK2, ATHL1, HSP90AA1 and ACTR2. 

CD4 T-cells also were found to infiltrate the lung tissue in the rat model, residing around lesioned tissue.

One of the most significant hub genes, ROCK2, has been linked previously to cellular processes implicated in PAH and has emerged as a potential therapeutic target for inflammatory diseases, including pulmonary fibrosis.

Using computational methods, the scientists found 20 existing molecules which could bind to the ROCK2 protein and possibly influence its function in PAH. Some of these molecules are already in clinical use for other conditions, namely certain types of cancer.

One identified ROCK2 inhibitor, called TDI0193, is structurally comparable to an investigational compound that is currently in clinical trials for pulmonary fibrosis.

Researchers call for more trials of ROCK2 gene inhibitors

“ROCK2 inhibitors show promise as a novel therapeutic approach for PAH,” the researchers wrote. “However, further clinical trials are needed to evaluate their safety and efficacy in larger patient populations.”

Along with ROCK2, ATHL1, HSP90AA1 and ACTR2 also could represent potential immune targets for preventing pulmonary vascular remodeling in PAH.

Despite this immune signature, the researchers noted it still is not completely known whether inflammation drives vascular remodeling, or is a consequence of it.

Nevertheless, “the detailed molecular mechanisms associated with these four genes should be further addressed elaborately in the future,” the scientists wrote.

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