Platelet-derived growth factor inhibition in idiopathic and familial pulmonary arterial hypertension

Pulmonary arterial hypertension is an unusual but devastating condition. It typically affects young women who present with increasing breathlessness on exertion and leads to death within a few years from diagnosis. Current therapies can give some improvement in symptoms but most patients eventually die of the disease. Recent advances in our understanding of the genetic and molecular basis of pulmonary arterial hypertension have identified some key growth factor pathways which are abnormal in the lung blood vessels of these patients. Amongst these, the platelet-derived growth factor (PDGF) pathway shows promise as a new target for treatment. Orally available and well tolerated drugs already exist which target this pathway in other diseases. We propose to study the therapeutic potential of a drug which inhibits the PDGF pathway in patients with severe pulmonary hypertension. In addition, we will undertake studies in cells derived from these patients to increase our understanding of how this drug works in pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a devastating condition which affects predominantly women of child-bearing age. Death typically ensues from right heart failure within 3 years without modern treatments. Available treatments improve symptoms of breathlessness but survival remains poor. Mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR-II) underlie 70% of cases of familial PAH, and 25% of apparently ?sporadic? cases of PAH. Our group, and others, have provided evidence that dysfunctional BMP signalling underlies various forms of severe PAH. These genetic findings have suggested a critical role for the BMP/TGF-beta superfamily in the pathogenesis of severe PAH. Our laboratories have shown that missense mutations in the functional domains of BMPR-II reduce the efficiency of Smad1 activation and the transcription of BMP responsive genes. In addition, suppression of BMP signalling allows exaggerated growth responses to transforming growth factor-beta (TGF-beta). Our preliminary data suggest that the exaggerated growth response to TGF-beta in mutant cells occurs via activation of platelet-derived growth factor (PDGF) receptors. Animal studies in rat models of PAH, and a single case study in man, have shown that the orally available PDGF receptor kinase inhibitor, imatinab, can reverse established pulmonary hypertension. This drug is currently licensed for the treatment of chronic myeloid leukaemia and is generally well tolerated. This proposal seeks to demonstrate in a proof of concept study whether a 6 month trial of imatinib versus placebo demonstrates safety and efficacy in the treatment of severe pulmonary arterial hypertension. In addition, we propose to demonstrate the molecular basis of the PDGF-dependent proliferation in relevant cells derived patients with idiopathic and familial PAH. To undertake these mechanistic studies we have established techniques to derive endothelial progenitor cells (EPCs) from patients and controls. The BMPR-II mutation status of all samples will be determined. Both early and late outgrowth EPCs will be characterised and used for in vitro studies of cell proliferation, tube formation and migration. BMP/TGF-beta signalling pathways and PDGF ligand and receptor expression and signalling will be determined. The mechanism of action of imatinib will also be investigated in these cells. This study will provide novel mechanistic insight into the pathogenesis of PAH. The proof of concept trial will be the first targeted growth factor therapy in severe PAH and may provide evidence for efficacy of this approach in man.