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My research focuses on the importance of the Bone Morphogenetic Protein Receptor 2 (BMPR2) signaling pathway in pulmonary, pulmonary-vascular as well as cardiac disease. In 2000 two independent groups discovered mutations in the BMPR2 pathway as the genetic basis for pulmonary arterial hypertension (PAH). Over the past years more mutations either directly involved in the BMPR2 pathway (Endoglin, ALk1, Smad9) or indirectly linked to the BMPR2 pathway (Caveolin-1) have been discovered, emphasizing the central role of BMPR2 signaling in familial PAH. It was subsequently found that reduced BMPR2 expression and signaling seems to be a feature of other sporadic or idiopathic forms of PAH. Hypothesizing that increasing BMPR2 signaling might improve PAH, we have performed a High-Throughput Screen of FDA approved drugs to find BMPR2 activators and have identified the immuno-suppressive drug FK506 (Tacrolimus) as as the main activator. We have subsequently shown that FK506 could rescue endothelial dysfunction in PAH, and prevent and reverse PAH in rodent models of experimental PAH (Spiekerkoetter JCI 2013). This discovery has lead to the initiation of a phase II clinical trial to test the safety, tolerability and efficacy of low-dose FK506 in PAH at Stanford (http://www.clinicaltrials.gov NCT01647945)My current research focuses on : 1. Novel ways how to modulate BMPR2 signaling (small molecule HTS screen, identifying novel modifier genes)2. Evaluating the importance of BMPR2 signaling in the development of Right Ventricular Hypertrophy (RVH) and failure, which is the leading cause of death in PAH (Collaboration with Dres Sushma Reddy and Daniel Bernstein, Pediatric Cardiology, Stanford). 3. Evaluating the importance of BMPR2 signaling in vascular development in neonatal chronic lung disease (Collaboration with Dr. Anne Hilgendorff, Helmholz Institute, Muenchen, Germany).
FK506 (Tacrolimus) in Pulmonary Arterial Hypertension
Mutations in bone morphogenetic protein receptor 2 (BMPR2) are present in >80% of familial
and ~20% of sporadic pulmonary arterial hypertension (PAH) patients. Furthermore
dysfunctional BMP signaling is a general feature of pulmonary hypertension even in
We therefore hypothesized that increasing BMP signaling might prevent and reverse the
disease. We screened > 3500 FDA approved drugs for their propensity to increase BMP signaling
and found FK506 (Tacrolimus) to be a strong activator of BMP signaling. Tacrolimus restored
normal function of pulmonary artery endothelial cells, prevented and reversed experimental
PAH in mice and rats.
Given that Tacrolimus is already FDA approved with a known side-effect profile, it is an
ideal candidate drug to use in patients with pulmonary arterial hypertension.
The aims of our trial are:
1. Establish the Safety of FK506 in patients with PAH.
2. Evaluate the Efficacy of FK506 in PAH
3. Identify ideal candidates for future FK506 phase III clinical trial.
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