A group of scientists in the United Kingdom published a paper in Nature Communications this week on what they hope may be a future potential therapy, based on their pre-clinical work studying a protein known to be elevated in patients with pulmonary arterial hypertension (PAH).
PAH is a rare disease characterized by high blood pressure of the lungs. In most people with PAH, the high blood pressure in the lungs occurs because the pulmonary arteries become stiffer and narrower than in people without PAH. Generally, this is due to an overgrowth of cells that make up the blood vessels in the lungs. Scientists do not exactly know what causes these changes in the cells and overgrowth. However, many are working to better understand why this occurs in some patients, what makes it worse in some patients, and whether this knowledge can lead to new PAH-targeted therapies.
Osteoprotegerin (OPG) is a substance in the body, called a protein, that has been shown to be important in maintaining bone density. Higher and lower than normal levels of OPG have been associated with other diseases in certain patients, including certain cancers, heart diseases, immune system diseases, diabetes and pregnancy issues.
Scientists interested in pulmonary hypertension (PH) have studied OPG as it is part of a larger “superfamily” of proteins implicated in PAH called tumor necrosis factor (TNF) receptors. When scientists have measured OPG levels in the lungs and blood of people with idiopathic PAH (IPAH), they noticed that the OPG levels were higher in people with IPAH than people without PAH.
Other scientists have studied OPG in mice that have been given PAH in the laboratory. A group of scientists reported in 2008 that mice without OPG might have PAH that is not as severe as mice with OPG who had PAH. The U.K. scientists who completed the work published this week also found in earlier studies that the severity of PAH increased in rats with PAH depending on the level of OPG.
With all of this information, a group of scientists—led by Miss Nadine Arnold and Professor Allan Lawrie at the University of Sheffield—wanted to know if reducing the levels of OPG in mice with PAH would improve their disease. A positive result could lead scientists to study this further as a potential treatment strategy for people with PAH. The scientists concluded that there was good reason to believe that OPG had an impact on development and severity of PAH and could someday be pursued as a potential therapy.
To come to this conclusion, the scientists first completed experiments where they removed OPG from a variety of mice using an antibody. An antibody is a protein that identifies and sticks to another specific substance (like OPG), allowing the body to “see” it and remove it. They found that mice with PAH treated with this antibody had signs of less severe PAH.
OPG is made by many different tissues in the body. The scientists next tried to better understand whether OPG that comes from a specific tissue has an impact on the development of PAH. They found that OPG specifically from the bone-marrow was related to PAH development and severity in these mice.
Since PAH is a disease of the pulmonary arteries, the scientists next wanted to better understand how OPG that was produced by the bone-marrow interacted with the cells that make the pulmonary arteries. They found that the presence of OPG was associated with changes in biological pathways that are known in PAH, including TGF-ß, cytoskeleton organization and cell survival pathways. These changes could explain why the PAH in these mice with OPG was more severe.
Though increased levels of OPG have been associated with severity of PAH, OPG is an important chemical. Removing OPG has been shown to result in osteoporosis in animal models. Therefore, the scientists wanted to learn more about how OPG interacts with the cells of the pulmonary arteries. By better understanding how OPG interacts with the cells of the pulmonary arteries, the scientists might be able to select an antibody that keeps some OPG working as it should, while reducing some of the “PAH interactions” in the pulmonary arteries. Through this process, the scientists identified an antibody called “Ky3” as a potential antibody to test further.
Finally, the scientists tested Ky3 in mice with PAH to see if there were any changes in their disease. They tested Ky3 and a placebo, along with PAH-therapies that are frequently used, sildenafil and bosentan, in similar types of mice. They found that treatment with Ky3 reduced the severity of PAH, as did currently used PAH-therapies sildenafil and bosentan.
The scientists believe that, after further study and if used, OPG might be useful alongside existing PAH-treatments rather than a “standalone” therapy. Much further research would need to be completed before an “OPG-antibody treatment” might be available in humans. This research includes understanding if OPG acts the same way in humans as it did in the mice studied by the University of Sheffield in this paper, whether it is safe to change the OPG levels in humans, and finally whether changing OPG levels has the same effect on humans as it did mice.
Importantly, the stage of research reported in this article is called pre-clinical research. Many therapies tested in the laboratory do not act the same way when they are tested in humans, and therefore must be carefully tested further. In their paper, the University of Sheffield reported that “We are currently exploring the potential for translation of this human therapeutic anti-OPG antibody to clinical studies in PAH.”
Funding for the research was provided by the British Heart Foundation, Medical Research Council, Wellcome Trust, AMKR, National Institute for Health Research Sheffield Cardiovascular Biomedical Research Unit and Cambridge National Institute of Health Research Biomedical Research Centre.