Production of endothelial no-synthase gene-enhanced autologous progenitor cell therapies for cardio-pulmonary diseases

      Endothelial progenitor cells (EPCs) derived from the circulation hold promise for the treatment of cardiovascular diseases. Yet preclinical studies suggest that patient derived cells are less effective stimulators of vascular repair. We have therefore pioneered the development of gene enhanced autologous cell based treatments for pulmonary hypertension and myocardial ischemia. Our first-in-human clinical trial (PHACeT, Pulmonary Hypertension: Assessment of Cell Therapy, NCT00469027) was a dose escalation safety trial using peripheral blood derived early outgrowth EPCs transiently transfected via electroporation with a human eNOS plasmid and delivered directly to the pulmonary circulation. We demonstrated that administration of eNOS-transfected EPCs to patients with stable, severe PAH was well tolerated, and resulted in a trend towards short-term hemodynamic improvement. Although, there was no long term sustained hemodynamic improvement in this small (7 patient), uncontrolled trial; there were significant increases in 6 minute walk time seen at both 1 month, and persisting to 3and 6 months post cell based gene therapy. To apply our therapy to cardiac patients we developed a non-mobilized automated apheresis procedure combined with GMP manufacturing in environmentally controlled isolator units and in addition adopted a cationic polymer (manose modified linear polyethylenimine) for eNOS transfection to limit cellular manipulations. Enhanced eNOS expression was verified by Western Blotting and cell identity by flow cytometry. With these manufacturing modifications in place a placebo controlled randomized trial (Enhanced Angiogenic Cell Therapy-Acute Myocardial Infraction trial, NCT00936819) testing the role of eNOS transfection in autologous EPCs was initiated with 4 patients treated to date. Our early results suggest that eNOS transfected autologous EPCs are safe and potentially effective treatments for cardiovascular disorders.
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