Pulmonary hypertension (PAH) is an insidious disease. Its symptoms may start slowly, and even before the symptoms appear, extensive damage has caused the blockage of small arteries, resulting in increased blood pressure in the lungs. When the symptoms—the most obvious being shortness of breath—are severe enough for PAH patients to seek treatment and obtain a definite diagnosis, based on currently available treatments, the patient’s chance of survival within five years is slightly higher than 50%.

Dr. Paul B. Yu, an expert in cardiovascular medicine at Brigham and Women’s Hospital in the United States, has studied PAH for more than 15 years, aiming to better understand the basic process of loss of Blood Vessels in the lungs due to this disease. In a new study, Dr. Yu and his research team clarified the biological pathways that may lead to the destruction of blood vessels. Their findings provide a biological explanation for why activin and growth and differentiation factor (GDF) may cause pulmonary vascular disease, and how activin/GDF blocking drug sotatercept, which is currently undergoing clinical trials, to help treat patients with PAH. Related research results were recently published in the journal Science Translational Medicine, with the title of the paper “ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension”.

Yu said, “We are excited to contribute to the preclinical validation of sotatercept and improve our understanding of the signaling molecules that drive PAH. We hope these advances will bring new treatment options to this extremely troublesome disease.”

Currently, PAH is treated with vasodilators to expand blood vessels in the lungs and increase blood flow. Yu and his research team have discovered new biological insights that may help more directly affect the course of this disease. Previous studies have found that PAH has a heritable form-mutations in certain genes that may affect the development, maturation, and remodeling of arterial circulation. These genes are involved in two pathways: bone morphogenetic protein (BMP) signaling pathway and transforming growth factor-β (TGFβ) signaling pathway. Some people believe that BMP has a protective effect, while higher levels of TGF-β have a destructive effect, but the specific mechanism is still unclear. There are also signs that two other closely related ligands, namely GDF and activin, are also involved. These two ligands play an important role in reproductive biology, but what role do they play in the context of PAH?

In this new study, Yu and colleagues provided data from human and rodent models in order to link these different protein participants together. They found that the levels of activin A and GDF8 increased in the lung lesions of PAH patients and rodent PAH models, and the level of GDF11 increased to a lesser extent. They then tested what happens when they add a “ligand trap” – a fusion protein that can trap GDF and activin to block their activity. They found that this fusion protein is more effective than vasodilators in treating PAH and blocking vascular remodeling, because it can restore a more normal balance between the proliferation and death of the cells that make up the blood vessel wall. When the mouse model is treated in the advanced stage of the disease, despite the previous damage, the treatment increases the number of open lung blood vessels, while vasodilators have no such effect.

Dr. Peiran (Brian) Yang, a member of the Yu team, said, “The discovery that GDF and activin play such a prominent role in PAH is unexpected, but if they help cause pulmonary vascular disease, then this may help explain the targeting therapies with these ligands may be effective in the treatment of PAH. Our research confirms that this genetic pathway that is essential for PAH is traceable and can be used as a drug target.”

Currently, this ligand trap is being studied as a method of treating PAH. Like a human version of this ligand trap, sotatercept was recently awarded “Orphan Drug” and “Breakthrough Therapy” by the US Food and Drug Administration (FDA).

As the manufacturing company of sotatercept, Acceleron Pharma recently announced the results of the phase 2 clinical trial of PULSAR for patients with PAH. Compared with placebo, patients treated with sotatercept had a significant reduction in pulmonary vascular resistance (PVR), which is the primary endpoint of this clinical trial. The second phase 2 clinical trial, SPECTRA, sponsored by Acceleron Pharmaceuticals and partly led by researchers at Brigham and Women’s Hospital, will continue to evaluate the efficacy and safety of sotatercept in patients with PAH. The SPECTRA clinical trial is ongoing and patients are currently being recruited.

Yu said, “There are still many unsolved mysteries, but with the changes in the degree of clinical relevance observed in clinical trials, coupled with our deeper understanding of the biology of this disease, what causes this disease and how we might use this knowledge to treat it is being connected in a coherent way.”

Reference

1. Lai-Ming Yung et al. ACTRIIA-Fc rebalances activin/GDF versus BMP signaling in pulmonary hypertension. Science Translational Medicine, 2020, doi:10.1126/scitranslmed.aaz5660.

2. Fusion protein holds promise for treating pulmonary arterial hypertension. https://medicalxpress.com/news/2020-07-fusion-protein-pulmonary-arterial-hypertension.html