Endothelial NO-Synthase Gene-Enhanced Progenitor Cell Therapy for Pulmonary Arterial Hypertension: The PHACeT Trial

John Granton; David Langleben; Michael B Kutryk; Nancy Camack; Jacques Galipeau; David W Courtman; Duncan J Stewart

doi:10.1161/CIRCRESAHA.114.305951

Endothelial NO-Synthase Gene-Enhanced Progenitor Cell Therapy for Pulmonary Arterial Hypertension: The PHACeT Trial

Circ Res. 2015 Sep 11;117(7):645-54. doi: 10.1161/CIRCRESAHA.114.305951. Epub 2015 Jul 20.

Authors

John Granton¹, David Langleben¹, Michael B Kutryk¹, Nancy Camack¹, Jacques Galipeau¹, David W Courtman¹, Duncan J Stewart²

Affiliations

¹ 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.).
² 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.

PMID: 26195220
DOI: 10.1161/CIRCRESAHA.114.305951

Abstract

Rationale: 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.

Methods and 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.

Conclusion: 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.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00469027.

Keywords: cell- and tissue-based therapy; endothelial progenitor cells; genetic therapy; hemodynamics; hypertension, pulmonary.

Publication types

Clinical Trial, Phase I
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Female
Humans
Hypertension, Pulmonary / enzymology
Hypertension, Pulmonary / genetics*
Hypertension, Pulmonary / therapy*
Male
Middle Aged
Nitric Oxide Synthase Type III / administration & dosage*
Nitric Oxide Synthase Type III / genetics*
Stem Cell Transplantation / methods*
Stem Cells / enzymology

Substances

NOS3 protein, human
Nitric Oxide Synthase Type III

Associated data

ClinicalTrials.gov/NCT00469027