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Pulmonary arterial hypertension - progress in understanding the disease and prioritizing strategies for drug development

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Title: Pulmonary arterial hypertension - progress in understanding the disease and prioritizing strategies for drug development
Authors: Ghataorhe, P
Rhodes, CJ
Harbaum, L
Attard, M
Wharton, J
Wilkins, MR
Item Type: Journal Article
Abstract: Pulmonary arterial hypertension (PAH), at one time a largely overlooked disease, is now the subject of intense study in many academic and biotech groups. The availability of new treatments has increased awareness of the condition. This in turn has driven a change in the demographics of PAH, with an increase in the mean age at diagnosis. The diagnosis of PAH in more elderly patients has highlighted the need for careful phenotyping of patients and for further studies to understand how best to manage pulmonary hypertension associated with, for example, left heart disease. The breadth and depth of expertise focused on unravelling the molecular pathology of PAH has yielded novel insights, including the role of growth factors, inflammation and metabolic remodelling. The description of the genetic architecture of PAH is accelerating in parallel, with novel variants, such as those reported in potassium two-pore domain channel subfamily K member 3 (KCNK3), adding to the list of more established mutations in genes associated with bone morphogenetic protein receptor type 2 (BMPR2) signalling. These insights have supported a paradigm shift in treatment strategies away from simply addressing the imbalance of vasoactive mediators observed in PAH towards tackling more directly the structural remodelling of the pulmonary vasculature. Here, we summarize the changing clinical and molecular landscape of PAH. We highlight novel drug therapies that are in various stages of clinical development, targeting for example cell proliferation, metabolic, inflammatory/immune and BMPR2 dysfunction, and the challenges around developing these treatments. We argue that advances in the treatment of PAH will come through deep molecular phenotyping with the integration of clinical, genomic, transcriptomic, proteomic and metabolomic information in large populations of patients through international collaboration. This approach provides the best opportunity for identifying key signalling pathways, both as potential drug targets and as biomarkers for patient selection. The expectation is that together these will enable the prioritization of potential therapies in development and the evolution of personalized medicine for PAH.
Issue Date: 19-May-2017
Date of Acceptance: 1-May-2017
URI: http://hdl.handle.net/10044/1/51329
DOI: https://dx.doi.org/10.1111/joim.12623
ISSN: 0954-6820
Publisher: Wiley
Start Page: 129
End Page: 141
Journal / Book Title: Journal of Internal Medicine
Volume: 282
Issue: 2
Copyright Statement: © 2017 The Association for the Publication of the Journal of Internal Medicine. This is the accepted version of the following article, which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1111/joim.12623/abstract
Sponsor/Funder: GlaxoSmithKline Services Unlimited
British Heart Foundation
British Heart Foundation
Funder's Grant Number: COL011953
RG/10/16/28575
FS/15/59/31839
Keywords: Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
drug development
genetics
metabolome
pathophysiology
personalized medicine
pulmonary hypertension
BRAIN NATRIURETIC PEPTIDE
RIGHT-VENTRICULAR FUNCTION
TO-MESENCHYMAL TRANSITION
RIGHT-HEART-FAILURE
CIRCULATING BIOMARKERS
REVEAL REGISTRY
FOLLOW-UP
MOLECULAR-MECHANISMS
PREDICTING SURVIVAL
PRECISION MEDICINE
Biomarkers
Genetic Predisposition to Disease
Hemodynamics
Humans
Hypertension, Pulmonary
Ventricular Function, Right
1103 Clinical Sciences
Cardiovascular System & Hematology
Publication Status: Published
Open Access location: http://onlinelibrary.wiley.com/doi/10.1111/joim.12623/epdf
Appears in Collections:Department of Medicine
Faculty of Medicine



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