Grant: Project Grant

Pulmonary arterial hypertension is a progressive condition characterized by the chronic elevation of pulmonary artery (PA) pressure leading to failure of the heart. In spite of recent advances in approved therapies, PAH remains a serious disease with significant mortality. In contrast to the earlier belief that contraction of pulmonary vessels played a key role in PAH, it is now established that excessive proliferation of the cells within the pulmonary artery wall is a pivotal component of pulmonary vascular obliteration, a currently irreversible feature of PAH for which available pharmacotherapies have no/limited efficacy. In recently years, it has become increasingly appreciated that, contrary to normal cells, these cells are exposed to stressful conditions, jeopardizing their survival. To deal with these insults, these cells have developed pathways, allowing them to survive and proliferate and leading to intense remodelling of pulmonary vessels. Central to these strategies are the activation of the mechanisms that repair DNA. We recently documented that pharmacological inhibition of PARP1, the most important mechanism involved in DNA repair, reverses PAH in human cells and animal models of PAH. Very recently, Olaparib, an orally available PARP1 inhibitor, was shown to be safe, well tolerated and effective in treating cancers and was approved by Health Canada for the treatment of ovarian cancer. The time is thus right to translate our findings in human PAH. This proposal addresses a very novel and promising therapeutic avenue to treat and is one of the first step of personalized medicine in PAH. We propose an early phase clinical trial to determine whether: 1) PARP1 inhibition with olaparib is safe and effective; 2) patients' genes can predict the efficacy and the side effect profile of olaparib in adult patients with symptomatic PAH.