Grant: Operating Grant: Epigenetics Clinical Translation

Pulmonary arterial hypertension (PAH) 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 recent years, it has become increasingly appreciated that, in addition to rare mutations in genes, changes in their expression in the absence of changes in their structure (i.e. epigenetics) largely contributes to this phenomenon in PAH. Changes in gene expression influence numerous functions of the cells. We recently documented that by regulating genes known to be deregulated in PAH, Bromodomain-containing Protein-4 (BRD4) largely contributes to excessive cell proliferation and pulmonary vascular obliteration in PAH. More importantly, we observed that the pharmacological inhibition of BRD4, reverses PAH in human cells and animal models of PAH. Very recently, apabetalone, an orally available BRD4inhibitor, was shown to be safe, well tolerated and effective in treating cancers vascular cell proliferation leading to other types of vascular obliteration such as coronary artery disease. 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 steps of personalized medicine in PAH. We propose an early phase clinical trial to determine whether: BRD4 inhibition with apabetalone is safe and effective and; patients' characteristics can predict response to therapy in adult patients with symptomatic PAH.