Angiogenic Gene Therapy (AGENT) Trial in Patients With Stable Angina Pectoris

Abstract

Background — The angiogenic response to myocardial ischemia can be augmented in animal models by gene transfer with the use of a replication defective adenovirus (Ad) containing a human fibroblast growth factor (FGF) gene. Methods and Results — The objectives of the Angiogenic GENe Therapy (AGENT) trial were to evaluate the safety and anti-ischemic effects of 5 ascending doses of Ad5-FGF4 in patients with angina and to select potentially safe and effective doses for subsequent study. Seventy-nine patients with chronic stable angina Canadian Cardiovascular Society class 2 or 3 underwent double-blind randomization (1:3) to placebo (n=19) or Ad5-FGF4 (n=60). Safety evaluations were performed at each visit and exercise treadmill testing (ETT) at baseline and at 4 and 12 weeks. Single intracoronary administration of Ad5-FGF4 seemed to be safe and well tolerated with no immediate adverse events. Fever of <1-day duration occurred in 3 patients in the highest-dose group. Transient, asymptomatic elevations in liver enzymes occurred in 2 patients in lower-dose groups. Serious adverse events during follow-up (mean, 311 days) were not different between placebo and Ad5-FGF4. Overall, patients who received Ad5-FGF4 tended to have greater improvements in exercise time at 4 weeks (1.3 versus 0.7 minutes, P =NS, n=79). A protocol-specified, subgroup analysis showed the greatest improvement in patients with baseline ETT ≤10 minutes (1.6 versus 0.6 minutes, P =0.01, n=50). Conclusions — Results show evidence of favorable anti-ischemic effects with Ad5-FGF4 compared with placebo, and it appears to be safe. Angiogenic gene transfer with Ad5-FGF4 shows promise as a new therapeutic approach to the treatment of angina pectoris.

Adeno-associated virus (AAV)-7 and -8 poorly transduce vascular endothelial cells and are sensitive to proteasomal degradation

“…1 Recent clinical results for cardiovascular disease have generally been disappointing with only secondary endpoints being met. 2,3 This may, at least in part, be attributed to the mode of gene delivery and the vectors utilized. Most preclinical studies have utilized adenoviral vectors.…”

Melhora sintomática e da capacidade de exercício após o transplante autólogo, transendocárdico, de células mononucleares da medula óssea em pacientes com cardiopatia isquêmica grave, sustentada até o sexto mês de evolução

“…The objective demonstration of an improvement in perfusion is fundamental when dealing with techniques of angiogenesis, which, according to data in the literature, are highly susceptible to the placebo effect [13][14][15][16][17][18][19] . Recently, improvement in the symptoms of patients undergoing transmyocardial laser revascularization have been reported [7][8][9][10][11][12] ; those data, however, could not be confirmed in randomized, double-blind studies 56,57 .…”

“…Those strategies comprise the following: intermittent or long-term use of urokinase [3][4][5] ; neurostimulation 6 ; transmyocardial revascularization by use of laser or radiofrequency, or mechanical transmyocardial revascularization [7][8][9][10][11][12] ; and neoangiogenesis through implantation of endothelial growth factors [13][14][15][16][17][18][19][20] . However, none of those techniques, despite some years of development, has proved to be effective in changing the poor prognosis of those patients to justify its routine clinical use [7][8][9][10][11][12] .…”

Cardiovascular gene delivery: The good road is awaiting☆

“…The AGENT (angiogenic gene therapy trial) study has looked at the benefits of intracoronary delivery of adenoviral-FGF-4 in patients with chronic stable angina. Preliminary randomized results appear to demonstrate a benefit in treadmill tolerance, perfusion scanning, and angina [209][210][211]. Both the VEGF-2 and FGF-4 treatments are currently being investigated in larger randomized, placebo-controlled clinical trials.…”