2-HOBA for Treatment of Pulmonary Hypertension

PROJECT SUMMARY Although the ubiquity of metabolic problems in pulmonary hypertension (PH) has been known for more than a decade, a wealth of new details on the nature of this problem presents the opportunity for intervention. A combination of experimental work in cells and animals and early trials in humans, suggests that these metabolic problems are part of the causation for PH, and that inactivation of the mitochondrial lysine deacetylase SIRT3 is a central node in regulating the metabolic defects. A vicious cycle exists in which a triggering event or mutation increases reactive oxygen species (ROS), which produces reactive lipids, which adduct and inactivate SIRT3, causing metabolic changes that result in further increased ROS. Here, we break this cycle using 2-HOBA, a small molecule which can effectively soak up reactive lipids in vivo and has positive results in safety trials for other indications in humans, with some still ongoing. Effectiveness of 2-HOBA has already been established for the prevention of PH in mice, and the mechanism suggests it should be effective for reversal. Here, we prepare for human trials of 2-HOBA by testing its efficacy for reversal of established disease in two molecularly accurate mouse models alone or in combination with metformin, and by examining serum biomarkers of disease shared between humans and mice for early indications of response which can be used to guide human trials.NARRATIVE The literature and our preliminary data support the hypothesis that the metabolic defects that are required for progression of Pulmonary Hypertension (PH) are caused in part of by inactivation of key proteins by adduction of reactive lipids. These reactive lipids can be blocked by 2-HOBA, a compound already undergoing safety testing for other indications in human patients. In this project, we test the ability of 2-HOBA alone, or in addition to metformin, to reverse established disease in two mouse models, and determine biomarkers of early response which will help guide human clinical trials.