by Buck Institute

A new approach to a rare age-related lung and heart disease

By Eptisam Lambu and Alyssa Lanza, Dominican University Masters Students

Pulmonary arterial hypertension (PAH) is a rare disease that attacks the pulmonary arteries which carry oxygen to the lungs. The disease affects about 12 to 15 people per million, and has a three-year survival rate of 58%. Because PAH is a progressive disease which first presents with mild symptoms, people often defer seeking medical attention. In fact, many people go years without being diagnosed. That’s because early symptoms — like shortness of breath and fatigue — are mild or occur only during strenuous exercise, and not many people go to the doctor because they feel tired after exercising.

The fatigue can of course easily be mistaken for being out of shape, or just being tired, but for people with PAH, it is actually due to obstruction in the pulmonary arteries. In a healthy person, de-oxygenated blood flows back to the right chambers of the heart, which then gets pumped to the lungs through pulmonary arteries to become oxygenated. In PAH patients, obstruction in the pulmonary arteries causes hypertension, and over time the high blood pressure causes the right chambers of the heart to work harder, stressing the heart and sometimes resulting in serious complications like heart failure and arrhythmias (irregular heart rhythms).

Although people at any age can be affected, studies have shown that the incidence of PAH is on the rise in older populations. While PAH is always difficult to diagnose, it is a particular challenge in older people since it can be difficult to differentiate the early signs of PAH from common age-related declines in heart and lung function. Right now, there are no effective treatments for PAH. Available therapies have failed to reverse the disease pathology or reduce the mortality rate since they do not treat the underlying cause of the disease. The current primary standard of care is the use of vasodilators, which widen the narrowed, obstructed blood vessels and provide only temporary symptomatic relief. Unfortunately for many patients, the disease progresses until the only treatment option available is lung transplantation — which itself has high morbidity — or until they suffer heart failure.

The exact cause of PAH remains unknown, but about two decades ago, researchers identified mutations in a gene called bone morphogenetic protein receptor 2 (BMPR2) to be responsible for at least the heritable PAH. Another study showed that 80% of patients with heritable PAH and 20% of patients with unknown cause of PAH carry mutations in the BMPR2 gene. It is believed that mutations in the BMPR2 gene result in an abnormally high number of endothelial cells in the pulmonary arteries, which can lead to the obstruction in the arteries of PAH patients.

Researchers hypothesize that perhaps enhancing BMPR2 protein’s function in the endothelial cells will help alleviate PAH symptoms or even cure the disease. In 2015, Long et al. proposed the use of a ligand called BMP9 as a therapeutic strategy to enhance function of the BMPR2 protein and eventually reverse PAH. cells. They tested the effect of BMP9 on three different PAH mouse and rat models and showed that the ligand indeed reverses the established PAH in all animal models, highlighting its potential as a therapeutic agent for PAH in humans.

Will BMP9 be used for PAH patients anytime soon? In December 2018, the British drug discovery company Morphogen-IX announced they had formulated an engineered variant of BMP9 (called MGX292) as a potential treatment candidate for PAH and had raised $23.2 million to support the next steps of preclinical development. Clinical trials are expected to begin in 2021.

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