Although several small studies have shown promising results for gene therapy with endothelial growth factors, the safety and benefit of such treatment has remained unproved. The goal of the Euroinject One Trial was to evaluate such therapy (with plasmid-delivered VEGF-A₁₆₅) in a double-blind, randomized controlled trial of patients with stable angina who had exhausted all other treatment options.

Investigators at multiple centers enrolled a total of 80 patients: Half received 10 injections of growth factor into areas of documented left ventricular reversible ischemia, whereas the other half received the same plasmid but with the sequence for VEGF-165 deleted (see graphic of plasmid structure).

Characteristics of the two treatment arms were similar, with average age roughly 60 years, ejection fraction roughly 40-50%, and no differences in prevalence of diabetes, prior myocardial infarction, or prior revascularization procedure.

The primary endpoint was ventricular perfusion assessed with Spect imaging; the three experts who read all scans were blinded to treatment arm and time point (latter, baseline versus follow-up). Secondary endpoints were clinical outcomes such as number of anginal episodes per day and use of nitroglycerine.

When perfusion results were analyzed on an intention-to-treat basis, there was a large difference in improvement between actively treated patients and placebo treated patients. However, a relatively large placebo effect was noted. When patients who had coronary events during the follow-up period were excluded, the difference favoring gene therapy was enhanced.

Assessment of clinical outcomes also showed benefits of gene therapy: There was a significant difference in daily usage of nitroglycerine and a trend toward fewer anginal attacks per day, both favoring active treatment.

Plasma growth factor and C-reactive protein levels rose in both groups at 1 week after injection, probably due to injection-related trauma, but normalized afterward in placebo-treated patients. Growth factor levels remained high at 2 and 4 weeks in the active treatment group, confirming that transfection occurred in these patients. C-reactive protein levels fell in the active treatment group, indicating that transfection did not cause an inflammatory process in the treated myocardium.

In an additional analysis, investigators found that levels of stem cells involved in growth of new blood vessels (CD34 cells) were increased after injection in the active treatment group but not in patients who received placebo injections.

The investigators concluded that intramyocardial injection with growth factor (specifically, VEGF-A₁₆₅) improved perfusion of treated areas as well as clinical outcomes such as nitroglycerine use; there was no evidence of adverse side effects. In combination with the findings of other studies, gene therapy merits further investigation to evaluate whether it may become a routine treatment in the future for patients with severe coronary artery disease.