title: Endothelial NO-Synthase Gene-Enhanced Progenitor Cell Therapy for Pulmonary Arterial Hypertension: The PHACeT Trial.
abstract: BACKGROUND
  Pulmonary arterial hypertension (PAH) remains a progressive and eventually lethal disease characterized by increased pulmonary vascular resistance because of 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 preclinical evaluation in experimental models of PAH.
  
  
  OBJECTIVE
  The Pulmonary Hypertension and Angiogenic Cell Therapy (PHACeT) trial was a phase 1, dose-escalating clinical study of the tolerability of culture-derived endothelial progenitor cells, transiently transfected with endothelial nitric oxide synthase, in patients with PAH refractory to PAH-specific therapies.
  
  
  RESULTS
  Seven to 50 million endothelial nitric oxide synthase-transfected endothelial progenitor cells, 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 intensive care unit setting. Seven patients (5 women) 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 toward improvement in total pulmonary resistance during the 3-day delivery period. However, there was 1 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, 6-minute walk distance was significantly increased at 1, 3, and 6 months.
  
  
  CONCLUSIONS
  Delivery of endothelial progenitor cells overexpressing endothelial nitric oxide synthase was tolerated hemodynamically in patients with PAH. Furthermore, there was evidence of short-term hemodynamic improvement, associated with long-term benefits in functional and quality of life assessments. However, future studies are needed to further establish the efficacy of this therapy.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00469027.
authors.affiliation: From the Division of Respirology, Pulmonary Hypertension Program, University Health Network (J. Granton) and Division of Cardiology, Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital (M.B.K.), Department of Medicine, University of Toronto, Toronto, Ontario, Canada (J. Granton, M.B.K.); Center for Pulmonary Vascular Disease, Division of Cardiology, and Lady Davis Research Institute, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (D.L.); Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (N.C., D.W.C., D.J.S.); Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (D.W.C., D.J.S.); Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA (J. Galipeau); and Northern Therapeutics, Montreal, Quebec, Canada (D.W.C., D.J.S.).
authors.forename: John
authors.initials: J
authors.lastname: Granton
authors.affiliation: From the Division of Respirology, Pulmonary Hypertension Program, University Health Network (J. Granton) and Division of Cardiology, Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital (M.B.K.), Department of Medicine, University of Toronto, Toronto, Ontario, Canada (J. Granton, M.B.K.); Center for Pulmonary Vascular Disease, Division of Cardiology, and Lady Davis Research Institute, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (D.L.); Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (N.C., D.W.C., D.J.S.); Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (D.W.C., D.J.S.); Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA (J. Galipeau); and Northern Therapeutics, Montreal, Quebec, Canada (D.W.C., D.J.S.).
authors.forename: David
authors.initials: D
authors.lastname: Langleben
authors.affiliation: From the Division of Respirology, Pulmonary Hypertension Program, University Health Network (J. Granton) and Division of Cardiology, Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital (M.B.K.), Department of Medicine, University of Toronto, Toronto, Ontario, Canada (J. Granton, M.B.K.); Center for Pulmonary Vascular Disease, Division of Cardiology, and Lady Davis Research Institute, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (D.L.); Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (N.C., D.W.C., D.J.S.); Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (D.W.C., D.J.S.); Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA (J. Galipeau); and Northern Therapeutics, Montreal, Quebec, Canada (D.W.C., D.J.S.).
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kutryk
authors.affiliation: From the Division of Respirology, Pulmonary Hypertension Program, University Health Network (J. Granton) and Division of Cardiology, Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital (M.B.K.), Department of Medicine, University of Toronto, Toronto, Ontario, Canada (J. Granton, M.B.K.); Center for Pulmonary Vascular Disease, Division of Cardiology, and Lady Davis Research Institute, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (D.L.); Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (N.C., D.W.C., D.J.S.); Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (D.W.C., D.J.S.); Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA (J. Galipeau); and Northern Therapeutics, Montreal, Quebec, Canada (D.W.C., D.J.S.).
authors.forename: Nancy
authors.initials: N
authors.lastname: Camack
authors.affiliation: From the Division of Respirology, Pulmonary Hypertension Program, University Health Network (J. Granton) and Division of Cardiology, Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital (M.B.K.), Department of Medicine, University of Toronto, Toronto, Ontario, Canada (J. Granton, M.B.K.); Center for Pulmonary Vascular Disease, Division of Cardiology, and Lady Davis Research Institute, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (D.L.); Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (N.C., D.W.C., D.J.S.); Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (D.W.C., D.J.S.); Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA (J. Galipeau); and Northern Therapeutics, Montreal, Quebec, Canada (D.W.C., D.J.S.).
authors.forename: Jacques
authors.initials: J
authors.lastname: Galipeau
authors.affiliation: From the Division of Respirology, Pulmonary Hypertension Program, University Health Network (J. Granton) and Division of Cardiology, Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital (M.B.K.), Department of Medicine, University of Toronto, Toronto, Ontario, Canada (J. Granton, M.B.K.); Center for Pulmonary Vascular Disease, Division of Cardiology, and Lady Davis Research Institute, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (D.L.); Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (N.C., D.W.C., D.J.S.); Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (D.W.C., D.J.S.); Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA (J. Galipeau); and Northern Therapeutics, Montreal, Quebec, Canada (D.W.C., D.J.S.).
authors.forename: David W
authors.initials: DW
authors.lastname: Courtman
authors.affiliation: From the Division of Respirology, Pulmonary Hypertension Program, University Health Network (J. Granton) and Division of Cardiology, Keenan Research Center for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital (M.B.K.), Department of Medicine, University of Toronto, Toronto, Ontario, Canada (J. Granton, M.B.K.); Center for Pulmonary Vascular Disease, Division of Cardiology, and Lady Davis Research Institute, Jewish General Hospital, Department of Medicine, McGill University, Montreal, Quebec, Canada (D.L.); Ottawa Hospital Research Institute, Ottawa, Ontario, Canada (N.C., D.W.C., D.J.S.); Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada (D.W.C., D.J.S.); Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA (J. Galipeau); and Northern Therapeutics, Montreal, Quebec, Canada (D.W.C., D.J.S.). djstewart@ohri.ca.
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000008:administration & dosage* / Q000235:genetics*; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000201:enzymology
chemical_list: C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
keywords: cell- and tissue-based therapy; endothelial progenitor cells; genetic therapy; hemodynamics; hypertension, pulmonary