World’s First Clinical Trial Of Genetically-enhanced Stem Cell PAH Therapy Yields Promising Findings

World’s First Clinical Trial Of Genetically-enhanced Stem Cell PAH Therapy Yields Promising Findings

A team of Canadian researchers have published promising results of the first clinical trial in the world of a genetically enhanced stem cell therapy for pulmonary arterial hypertension (PAH).

This rare and deadly disease mainly affects young women, and is characterized by very high pressure in the arteries supplying blood to the lungs. In some cases, PAH is caused by a defective gene, but in many cases the cause is unknown. Currently available drugs can modestly improve symptoms and exercise capacity (at best), but cannot repair the blood vessel damage to the lungs or cure the disease.

The study entitled Endothelial NO-Synthase Gene-Enhanced Progenitor Cell Therapy for Pulmonary Arterial Hypertension: the PHACeT Trial (Circulation Research, 2015; CIRCRESAHA.114.305951 DOI: 10.1161/CIRCRESAHA.114.305951), published in the journal Circulation Research, is coauthored by John Granton of the University of Toronto’s Thoracic Surgery Labs, University Health Network; David Langleben of Jewish General Hospital CArdiology; Michael J Kutryk of St Michael’s Hospital at McGill University Cardiology in Montreal; Nancy Camack with Clinical Research Administration at the Ottawa Hospital Research Institute; Jacques Galipeau of the Winship Cancer Institute, Emory University; and David Courtman and lead investigator Duncan J. Stewart of the Ottawa Hospital Research Institute.

The coauthors describe pulmonary arterial hypertension (PAH) as a progressive and eventually lethal disease characterized by increased pulmonary vascular resistance due to loss of functional lung microvasculature, and note that cell-based therapies offer potential to make repairs and regenerate the lung microcirculation and have shown promise in pre-clinical evaluation in experimental models of PAH.

The trial was a phase 1, dose-escalating clinical study to test the tolerability, feasibility, and side-effects of a genetically-enhanced stem cell therapy to repair and regenerate lung blood vessels in PAH. Seven participant patients underwent a blood cell selection process (apheresis) to harvest a certain population of their white blood cells. These cells were grown in the laboratory under special conditions to select for stem-like cells called endothelial progenitor cells (EPCs) genetically engineered to produce greater amounts of nitric oxide, a natural substance that widens blood vessels and is essential for efficient vascular repair and regeneration. The genetically enhanced cells were then injected directly into the lung circulation of the same patient.

Seven patients (5 female) received treatment from December 2006 to March 2010. The researchers observed that cell infusion was well tolerated, with a trend towards improvement in total pulmonary resistance (TPR) over the three-day delivery period. However, there was one serious adverse event (death) that occurred immediately after discharge in a patient who had severe, end stage disease.

The investigators conclude that delivery of EPCs overexpressing eNOS was tolerated hemodynamically in patients with PAH, with evidence of short-term hemodynamic improvement, associated with long-term benefits in functional and QOL assessments. However, they caution that future studies will be needed in order to further establish the efficacy of this therapy.

Although the study was not designed to rigorously assess benefits the therapy might enable, the researchers observed improved blood flow in the lungs in the lungs of patients during days following the therapy, and enhanced ability to exercise and better quality of life for up to six months after the therapy. However, with no placebo control group in this study, it is impossible to determine for sure if effects observed were due to the cells or to psychological effects.

The therapy was generally well-tolerated, however one patient who had very severe and disease and signs of poor prognosis died one day after treatment, a not unexpected outcome, given the patient’s declining condition prior to treatment.

“Pulmonary arterial hypertension is a deadly and incurable disease that often strikes people in the prime of their life,” says the Circulation Research paper’s senior author Dr. Duncan Stewart, a practicing cardiologist and Executive Vice-President of Research at The Ottawa Hospital, and a professor of medicine at the University of Ottawa. “We desperately need new therapies for this disease, and regenerative medicine approaches have shown great promise in laboratory models and in clinical trials for other conditions.”

“This trial shows that genetically-enhanced stem cell therapy is a promising treatment approach for pulmonary arterial hypertension,” observes Dr. Stewart. “Although this is an important start, we will need to do larger studies to establish whether this therapy can produce important and durable benefits for people suffering from this challenging disease.”

Dr. Stewart is also leading the first clinical trial in the world of a genetically-enhanced stem cell therapy for heart attack.

The trial patients were recruited at St. Michael’s Hospital in Toronto and the Jewish General Hospital in Montreal. The study was funded by Northern Therapeutics and the Stem Cell Network.

Ottawa Hospital Research Institute
Circulation Research

Image Credits:
University of Ottawa
Ottawa Hospital Research Institute

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