BHF Senior Basic Science Research Fellow Head of Pulmonary Vascular Research Group Department of Infection, Immunity & Cardiovascular Disease University of Sheffield
Targeting the osteoprotegerin/TRAIL axis for the treatment of pulmonary arterial hypertension (PAH)"
Pulmonary Arterial Hypertension (PAH) is a fatal condition driven by sustained pulmonary vasoconstriction and progressive remodelling of the small pulmonary arteries that culminates in right heart failure. Osteoprotegerin (OPG) is increased within serum and pulmonary vascular lesions of patients with idiopathic PAH, and is a mitogen for pulmonary artery smooth muscle cells (PASMC). We have identified that the proliferative effect of OPG on PASMC is mediated via a novel OPG-Fas cell surface receptor protein interaction. Furthermore, we demonstrate that genetic deletion and/or antibody blockade of OPG both prevent and attenuate development of PAH in multiple rodent models. Finally, we demonstrate therapeutic efficacy with a novel human anti-human, monoclonal OPG antibody in a severe rat model of PAH. Targeting OPG represents a new treatment strategy in PAH with potential for clinical translation.