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

Lead Research Organisation: University of Cambridge
Department Name: Medicine


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.

Technical Summary

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.


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Ghofrani HA (2010) Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. in American journal of respiratory and critical care medicine

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Toshner M (2010) Endothelial progenitor cells in pulmonary hypertension - dawn of cell-based therapy? in International journal of clinical practice. Supplement

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Toshner M (2009) Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension. in American journal of respiratory and critical care medicine

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Toshner MR (2012) The fibrocyte in pulmonary hypertension: we seek him here, we seek him there. in The European respiratory journal

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Zhao J (2012) Late outgrowth endothelial progenitor cells engineered for improved survival and maintenance of function in transplant-related injury. in Transplant international : official journal of the European Society for Organ Transplantation

Description BHF Fellowship
Amount £120,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2007 
Title Endothelial progenitor cells 
Description Late outgrowth EPCs from controls and patients with pulmonary arterial hypertension 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2009 
Provided To Others? Yes  
Impact Availability of EPC s from patients with defined mutations in BMPR2 gene in familial pulmonary hypertension 
Description EU Framework 6 "PULMOTENSION" 
Organisation European Commission
Department EC FP6 Collaborative Projects
Country European Union (EU) 
Sector Academic/University 
PI Contribution Collaborative studies and expertise with endothelial progenitor cells
Collaborator Contribution Collaborative studies on endothelial progenitor cells
Impact Yang J, Li X, Al-Lamki RS, Southwood M, Zhao J, Lever AM, Grimminger F, Schermuly RT, Morrell NW.Smad-dependent and Smad-independent induction of ld1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo. Circulation Research 2010 Jun 3 [Epub ahead of print] PMID: 20522807. Toshner M, Voswinckel R, Southwood M, Al-Lamki R, Luke S, Howard LS, Marchesan D, Yang J, Suntharalingam J, Soon E, Exley A, Stewart S, Hecker M, Zhu Z, Gehling U, Seeger W, Pepke-Zaba J, and Morrell NW. Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension Am. J. Respir. Crit. Care Med. 2009;180 780-787.
Title Imatinib 
Description Imatinib was shown to be effective in severe PAH in the MRC sponsored experimental medicine study. the subsequent phase 3 study showed benefit but due to the side effect profile this is not being developed further by the company (Novartis). 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2010
Development Status On hold
Clinical Trial? Yes
Impact The study demonstrated that tyrosine kinase inhibition might be a useful approach in this rare and often fatal disease. Unfortunately the side effect profile was not favourable. Further studies will focus on more selective tyrosine kinases.