Repurposing FK506 to Increase BMPR2 Signaling and Improve Pulmonary Arterial Hypertension: A Fast Track From Cells to People

Abstract

To improve long-term survival in pulmonary arterial hypertension (PAH), new treatment approaches that target occlusive vasculopathy instead of vasoconstriction of pulmonary arteries are necessary. Identifying genes or pathways that unify different pathologies and etiologies in PAH is a crucial first step for drug development. The bone morphogenetic protein receptor 2 (BMPR2) pathway, originally described as the cause of familial PAH, has gained significant interest over the past few years as a potential master switch in PAH, and therefore presents a promising treatment target in PAH. FK506 (tacrolimus) was found in a high-throughput screen of US Food and Drug Administration (FDA)-approved drugs to significantly increase BMPR2 signaling. Low-dose FK506 was able to restore normal BMPR2 signaling and function in patient pulmonary artery (PA) endothelial cells, inhibit proliferation and induce apoptosis in PA smooth muscle cells, and prevent and reverse pulmonary hypertension (PH) in 3 experimental rodent models of PH. As an FDA-approved drug, it was possible to relatively quickly (in approximately 2 years) translate the basic science discoveries from the bench to the clinic. A Phase 2 proof-of-concept safety and tolerability trial is underway (ClinicalTrials.gov Identifier: NCT01647945) to evaluate the use of low-dose FK506 in PAH and to identify patients who might respond best to FK506 depending on their impairment in BMPR2 signaling.