Restoring levels of key protein eases PAH severity in preclinical models
Study: Biologic and gene therapy approaches reverse existing heart damage
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Restoring the levels of BMP3, a naturally occurring protein involved in cell communication that regulates pulmonary blood vessels, reversed key features of pulmonary arterial hypertension (PAH) in preclinical models, a study found.
Compared with people without PAH, levels of BMP3 were lower in lung tissue, smooth muscle cells that sit on pulmonary arterial walls, and blood samples from people with idiopathic (unknown cause) PAH. The same was seen in animal models of the disease.
When researchers restored BMP3 using either a lab-made BMP3 protein or a lung-targeted gene therapy, the disease became less severe, and right heart function improved.
“Most current therapies focus on managing symptoms or slowing disease progression. What makes this discovery exciting is that it identifies a new therapeutic strategy aimed at restoring a natural protective mechanism that is lost during disease,” Yassine Sassi, PhD, associate professor at Virginia Tech’s Fralin Biomedical Research Institute and the study’s senior author, said in a press release.
The study, “Paracrine action of bone morphogenetic protein 3 in pulmonary arterial hypertension,” was published in the European Respiratory Journal.
PAH linked to abnormal signaling of the BMP pathway
PAH is a rare and progressive disease in which the small blood vessels of the lungs become narrowed and thickened. This raises blood pressure in the lungs and forces the right side of the heart to work harder, which can eventually lead to heart failure.
The disease has been linked to abnormal signaling of the BMP pathway. Despite being considered a promising treatment target, only a few BMP ligands — proteins that bind to and activate receptors in the pathway — have been studied in PAH.
In adults, BMP3, also called osteogenin, is a member of the BMP family that is primarily produced in the lungs. However, its role in PAH remains poorly understood.
The researchers first found that BMP3 levels were reduced in rat and mouse models of PAH. They also found that BMP3 was mainly produced by pulmonary artery smooth muscle cells (PASMCs), which help form the vessel wall. These findings were confirmed in human lung samples, where BMP3 levels were lower in people with idiopathic PAH than in controls without the disease.
Since BMP3 was mainly produced by PASMCs, the researchers next tested whether it could act as a signal to nearby pulmonary artery endothelial cells (PAECs), which line the inside of blood vessels.
Lab experiments using human cells revealed that BMP3 reduced PAEC proliferation (growth and division) and migration — two processes that, when excessive, contribute to the abnormal changes in blood vessel structure (remodeling) seen in PAH.
Loss of BMP3 worsened disease in middle-aged mice
To further assess the role of BMP3, researchers deleted the gene responsible for producing the protein in mice and then induced PAH-like disease. They compared the effects in young and middle-aged animals. They found that loss of BMP3 had little effect in young animals, but worsened disease in middle-aged mice.
“These results demonstrated age-dependent effects of BMP3 by showing that a global deletion of BMP3 sensitizes the pulmonary vasculature [blood vessels] and exacerbates PH in middle-aged mice, but not in young animals,” the scientists wrote.
The researchers then tested whether restoring BMP3 could counter PAH-induced changes. In mice, treatment with lab-made BMP3 helped prevent PAH-like features when given before disease was induced. It also showed benefit when given after the disease had already developed.
The team next used a gene therapy approach to increase BMP3 production directly in the lungs. This strategy also led to marked improvements in the animals’ lungs and heart, reducing pulmonary arterial pressure and decreasing enlargement of the heart that is seen in PAH.
This gives us two potential therapeutic paths forward: a biologic therapy [meaning it is made or contains components of a living organism] and a gene-based approach, both designed to restore a natural protective signal that is lost during disease.
Gene therapy also showed positive results in a severe rat model of PAH, where treatment was given after the disease had already developed. In that model, the therapy improved right heart function, reduced blood pressure in the lungs, and lessened pulmonary blood vessel remodeling.
“This gives us two potential therapeutic paths forward: a biologic therapy [meaning it is made or contains components of a living organism] and a gene-based approach, both designed to restore a natural protective signal that is lost during disease,” Sassi said.
The findings also raise the possibility that BMP3 could be explored as a blood-based biomarker, since circulating BMP3 was lower in people with PAH.
Sassi and first author Aymen Halouani, PhD, have filed a patent application covering BMP3-based therapeutic approaches for PAH, according to the press release.
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