Pulmonary arterial hypertension is a severe and life-limiting disease that affects the blood vessels in the lungs, leading to failure of the right side of the heart, and leaves sufferers feeling breathless and exhausted. Currently available treatments mainly target vasoconstriction of blood vessels. Although they help some of the symptoms of PAH, the overall prognosis remains poor.
The unmet need in PAH is clearly demonstrated by the fact that the mortality at 5 years is as high as 50%. The only effective cure is transplantation of the lungs or heart and lungs, which has associated risks and complications.
The pathobiology of PAH is characterised by endothelial dysfunction and abnormal muscularisation of pre-capillary arterioles resulting in an increased pulmonary vascular resistance. The pathology is characterised by the formation of concentric or plexiform vascular lesions leading to pruning and loss of pre-capillary vessels and a reduction in the surface area of the pulmonary vascular bed.
Evidence strongly supports the hypothesis that endothelial dysfunction plays a central role in the initiation and progression of PAH. Endothelial dysfunction includes endothelial cell apoptosis, increased angiogenesis, loss of endothelial barrier function and alteration in the release of vasoactive mediators.
Human genetic studies in PAH patients have identified that the most common causal genetic findings in PAH patients are mutations in the BMP9 signalling pathway, most commonly mutations in the bone morphogenetic protein type II (BMPR-II) receptor, which is the receptor for BMP9. Mutations causing reduced function of BMP9 itself have also been recently identified.
BMP9 is a circulating protein that selectively binds and activates BMPR-II receptor complexes on endothelial cells, as well as increasing the levels of BMPR-II. BMP9 protects endothelial cells from apoptosis, inhibits angiogenesis and improves endothelial barrier function.
Administration of exogenous BMP9 has been shown to augment endothelial BMPR-II signalling and reverse PAH in several rodent models of disease. This provides a strong rationale for developing BMP9-based therapies to target the underlying cellular mechanisms of PAH.
Our goal is to unleash the potential of BMP9-based proteins as a transformative therapy for PAH.