Pulmonary arterial hypertension (PAH) means you have high blood pressure in the small arteries carrying blood to the lungs. In the 1950s, many scientists started to describe how PAH ran in families, and realised that PAH can be inherited. But until 2000, no one knew which gene or genes were involved.
Finding the main culprit
In 2000, BHF-funded research led by Professor Richard Trembath at the University of Leicester showed that mutations in the gene BMPR2 caused inherited PAH. Today, we know that mutations in this gene are responsible for around 70% of inherited cases of PAH.
In 2001, Professor Trembath and Dr Nick Morrell (now BHF Professor of Cardiopulmonary Medicine at the University of Cambridge) built on this work, showing how changes in BMPR2 affect the blood vessels in the lungs and lead to PAH.
Since then, we have supported research that has shed more light on the role of BMPR2 in the development of PAH, as well as looking at how we can block those effects in order to stop or reverse the development of PAH.
In 2015, BHF Professor Morrell and his team identified a molecule that can stop the harmful effects of this change in the BMPR2 gene. They showed that in mice, this treatment can reverse PAH.
These results demonstrated the potential of targeting the effects of the BMPR2 gene mutation, in order to offer a new treatment for PAH. This work led to the creation of the spin-out company Morphogen-IX to develop new PAH treatments. The company aims to begin studies of these treatments in humans in 2021.
Creating a unique world-leading resource to study pulmonary arterial hypertension
With support from the BHF, Professor Morrell and UK PAH specialists have been following a large group of PAH patients and their families since 2013, collecting research data as well as information gathered from their usual tests and treatment. The group is still growing as new cases are identified.
This is an important resource, because although the presence of a BMPR2 gene mutation is the greatest risk factor for the development of PAH, it is estimated that only on in five people with a mutation develop the disease. So it could be that additional factors, either genetic or environmental, are needed for the condition to develop. Researchers are now aiming to identify those factors, to help provide better estimates of risk of developing PAH to relatives of those with the condition, as well as to identify new ways of treating this disease.
The resource can also help researchers identify other genes causing inherited forms of PAH. BHF-funded researcher Dr Chris Rhodes at Imperial College London, with Professors Martin Wilkins and Nick Morrell, have combined data from the UK patients with those from four large groups of patients from Europe and North America to identify common genetic mutations associated with PAH. This international collaboration analysed the genes of more than 11,000 people, making it the largest genetic study of PAH to date. In 2019, they identified common mutations in a second gene that is linked to having PAH. This gene is called SOX17.
The BHF is now funding Dr Rhodes to look further into exactly how SOX17 is involved in the development of PAH. This could lead to new and better treatments for this life-shortening disease.
First published 1st June 2021