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The limited treatment options for patients with end-stage pulmonary arterial hypertension (PAH) and right heart failure that I observed as a Pulmonary and Critical Care fellow at Hannover Medical School in Germany in the early 2000s were the reason I sought out basic research training in vascular biology under the mentorship of Dr. Marlene Rabinovitch at Stanford University. As a physician scientist I strive to better understand the pathogenesis and underlying pathobiology of pulmonary and cardiovascular diseases such as PAH, arteriovenous malformations in hereditary hemorrhagic telangiectasia (HHT) and right heart failure to develop more effective treatments for these diseases. We use 3-D deep tissue imaging, mouse mutants and lineage tracing approaches to answer questions about the molecular and anatomic structure of blood vessels in concert with the extracellular matrix in the lung and the heart in health and disease.A particular focus in my laboratory is the involvement of the BMPR2/TGF-b pathway in vascular biology. We use High-Throughput Screening techniques, induced pluripotent stem cells and bioinformatic approaches to identify and test repurposed and repositioned drugs that modulate BMPR2 signaling. By testing compounds in vitro and in vivo models of HHT and PAH, our ultimate goal is to identify candidates that would be promising to move forward into clinical trials. Our discoveries have led 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) as well as three patents for repurposed and repositioned drugs for the treatment of PAH and HHT. My laboratory values close collaboration of clinicians, translational as well as basic scientists to apply biological concepts to disease models, driven by the notion that we first need to understand processes in health and disease before we can intervene. The ultimate objective of the lab is to successfully realize bench-to-bedside research for our patients.
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.
Stanford is currently not accepting patients for this trial.
For more information, please contact Edda Spiekerkoetter, MD, 650-724-1493.
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