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 area of the pulmonary vascular bed.
Recent evidence strongly supports the hypothesis that endothelial dysfunction, driven by reduced BMPR-II signalling, 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.
Although existing therapies partly address the imbalance of vasoactive mediators, there remains a clear unmet need for developing novel therapies that target the underlying disease mechanisms of PAH.
For the past 15 years, the Morrell laboratory at Cambridge University has focussed its efforts on understanding the genetic basis of PAH, and particularly how loss-of-function mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR-II), the most common genetic cause of PAH, leads to disease.
In addition, this group was the first to demonstrate that loss of BMPR-II function is a unifying feature of both genetic and non-genetic forms of PAH. More recently, the group has spearheaded novel approaches to restore BMPR-II function as a therapeutic option in this disease.
The identification of BMP ligands that selectively target the dominant pathway implicated from human genetic studies, and proven in preclinical models of PAH, has major potential as a transformative therapy in this disease area.
In a series of preclinical studies, the Morrell laboratory team have shown that BMP9 treatment reversed established PAH in both genetic and non-genetic forms of the disease.
These results demonstrate the promise of direct enhancement of endothelial BMP signalling as a new therapeutic strategy for PAH.