PROJECT 3: The goal of this project is to prepare for a Phase II trial of recombinant ACE2 in human pulmonary arterial hypertension (PAH) patients. ACE2 is a recently discovered peptide which inactivates Angll to make Ang(1- 7);Ang(1-7) signals through the Masi receptor. ACE2 mechanism and consequences are thus distinct from ACE inhibitors and receptor blockers, as neither result in increased Ang(1-7) and Masi signaling. Recombinant ACE2 has already proven effective in blocking or treating established pulmonary arterial hypertension (PAH) in several rodent models, including in Bmpr2-mutation related PAH, and has already passed safety trials in healthy human subjects. Preliminary data suggests that the mechanism by which ACE2 treats PAH is through reversal of cytoskeletal defects common to both idiopathic and heritable PAH, including defects in steroid hormone receptor shuttling, endothelial barrier function, and cell-cell junctions. In HPAH, these defects are a consequence of all classes of BMPR2 mutation, which regulates the cytoskeleton through binding and phosphorylation of key cytoskeletal regulators LIMK1 and TCTEX1;however, these same defects have also been seen in IPAH, and so we hypothesize that they are a common cause of PAH. Because of the demonstrated safety of ACE2 use in healthy humans and the strong mechanistic and efficacy data in multiple mouse models, we think it is prudent and timely to test ACE2 in PAH patients.
In Aim 1, we propose confirming the molecular mechanism by which ACE2 treats PAH.
In Aim 2, we test the safety of ACE2 for prolonged use and withdrawal in mice.
In Aim 3, we carry out a phase lb, single-center, open- label, dose-escalation and multiple dose study to evaluate the safety and early indications of efficacy of rhACE2 in subjects with PAH. At the conclusion of this project, we anticipate preparation for a Phase II trial of ACE2 in human PAH patients.
Recombinant ACE2 is effective in treating multiple animal models of pulmonary arterial hypertension (PAH), by correcting defects in a pathway, cytoskeletal trafficking, not impacted by any existing treatment for PAH. In this study, we complete studies necessary to translate this finding to human patients, including confirmation of mechanism, long term safety studies, and safety and early efficacy studies in PAH patients.
|Best, D Hunter; Sumner, Kelli L; Austin, Eric D et al. (2014) EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest 145:231-6|
|Robbins, Ivan M; Hemnes, Anna R; Pugh, Meredith E et al. (2014) High prevalence of occult pulmonary venous hypertension revealed by fluid challenge in pulmonary hypertension. Circ Heart Fail 7:116-22|
|Brittain, Evan L; Hemnes, Anna R (2014) One generation's "junk" is another's treasure: the emerging role of microRNAs as therapeutic targets. J Heart Lung Transplant 33:233-4|
|Stearman, Robert S; Cornelius, Amber R; Lu, Xiao et al. (2014) Functional prostacyclin synthase promoter polymorphisms. Impact in pulmonary arterial hypertension. Am J Respir Crit Care Med 189:1110-20|
|Hemnes, Anna R; Brittain, Evan L; Trammell, Aaron W et al. (2014) Evidence for right ventricular lipotoxicity in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med 189:325-34|
|Zhao, Min; Austin, Eric D; Hemnes, Anna R et al. (2014) An evidence-based knowledgebase of pulmonary arterial hypertension to identify genes and pathways relevant to pathogenesis. Mol Biosyst 10:732-40|
|Austin, Eric D; Loyd, James E (2014) The genetics of pulmonary arterial hypertension. Circ Res 115:189-202|
|Brittain, Evan L; Pugh, Meredith E; Wheeler, Lisa A et al. (2013) Prostanoids but not oral therapies improve right ventricular function in pulmonary arterial hypertension. JACC Heart Fail 1:300-7|
|Brittain, Evan L; Pugh, Meredith E; Wang, Li et al. (2013) Predictors of diastolic-to-wedge gradient in patients evaluated for pulmonary hypertension. PLoS One 8:e76461|
|Austin, Eric D; Loyd, James E (2013) Heritable forms of pulmonary arterial hypertension. Semin Respir Crit Care Med 34:568-80|