Seeking the right targets: gene therapy advances in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a grave vascular disorder characterised by the obstruction and occlusion of the small pulmonary arteries, primarily through the abnormal proliferation of the endothelial and smooth muscle layers. A clinical diagnosis of pulmonary hypertension (PH) is made when the mean pulmonary arterial pressure ( P pa) is ≥25 mmHg at rest. An additional criterion to differentiate PAH from other forms of PH requires that pulmonary arterial wedge pressure be ≥15 mmHg [1, 2]. The disease is typically fatal due to right heart failure as a result of the pathological increases in pulmonary vascular resistance. While the majority of the patient population develop spontaneous or idiopathic PAH and PAH associated with other disorders, for example, HIV infection, connective tissue disease or exposure to risk factors such as appetite suppressants containing dex/fenfluramine (associated PAH), some 10% display familial transmission. In families, PAH is an autosomal dominant trait with a sex bias favouring females and penetrance as low as 20%, features that suggest that, while a Mendelian condition, PAH displays features of complex disease [1, 2]. Traditional positional cloning approaches identified the causative gene for familial PAH as BMPR2 , encoding a type-II receptor of the transforming growth factor (TGF)-β signalling family [3, 4]. Currently, deleterious germ-line mutations have been detected in ∼70% of families analysed and 25% of idiopathic cases [5, 6]. The recent re-classification of mutation carriers with or without a family history as heritable PAH (HPAH), at the 4th World symposium on Pulmonary Hypertension (Dana Point, CA, USA) in 2008, indicates the growing recognition of the central importance of BMPR2 dysfunction in pathogenesis [7]. The majority of BMPR2 mutation in HPAH predicts premature truncation of the transcript and, …