Endothelial NO-Synthase Gene-Enhanced Progenitor Cell Therapy for Pulmonary Arterial Hypertension: the PHACeT Trial
Rationale: Pulmonary arterial hypertension (PAH) remains a progressive and eventually lethal disease characterized by increased pulmonary vascular resistance due to loss of functional lung microvasculature, primarily at the distal (intracinar) arteriolar level. Cell-based therapies offer the potential to repair and regenerate the lung microcirculation and have shown promise in pre-clinical evaluation in experimental models of PAH.
Objective: The Pulmonary Hypertension And Cell-Therapy (PHACeT) trial was a phase 1, dose-escalating clinical study of the tolerability of culture-derived endothelial progenitor cells (EPCs), transiently transfected with endothelial NO-synthase (eNOS), in patients with PAH refractory to PAH-specific therapies.
Methods and Results: Seven to 50 million eNOS-transfected EPCs, divided into 3 doses on consecutive days, were delivered into the right atrium via a multiport pulmonary artery catheter during continuous hemodynamic monitoring in an ICU setting. Seven patients (5 female) received treatment from December 2006 to March 2010. Cell infusion was well tolerated, with no evidence of short-term hemodynamic deterioration; rather, there was a trend towards improvement in total pulmonary resistance (TPR) over the three-day delivery period. However, there was one serious adverse event (death) which occurred immediately after discharge in a patient with severe, end stage disease. Although there were no sustained hemodynamic improvements at 3 months, 6MWD was significantly increased at 1, 3 and 6 months.
Conclusions: Delivery of EPCs overexpressing eNOS was tolerated hemodynamically in patients with PAH. Furthermore, there was evidence of short-term hemodynamic improvement, associated with long-term benefits in functional and QOL assessments. However, future studies are needed to further establish the efficacy of this therapy.
- pulmonary hypertension
- stem cell
- clinical trial
- endothelial nitric oxide synthase
- endothelial progenitor cells
- Received December 27, 2014.
- Revision received July 13, 2015.
- Accepted July 17, 2015.