Angiogenic gene therapy with adenovirus 5 fibroblast growth factor-4 (Ad5FGF-4): a new option for the treatment of coronary artery disease.
Angiogenic gene therapy for stable angina is aimed at promoting new blood vessel formation in the heart, thus providing enhanced cardiac perfusion, symptom relief, increased exercise capacity, improved quality of life, and reduced risk of coronary events. Ad5FGF-4 is a replication-deficient serotype 5 adenovirus encoding the gene for fibroblast growth factor-4 (FGF-4) driven by a cytomegalovirus promoter. In preclinical studies using a pig model of myocardial ischemia, a single intracoronary infusion of Ad5FGF-4 improved cardiac contractile function and regional blood flow in the ischemic region during stress. These effects were apparent after 2 weeks and maintained for > or =12 weeks. Histologic evidence of capillary angiogenesis was observed. FGF-4 gene expression was detected in the heart but not at extracardiac sites. Placebo-controlled trials in humans with chronic stable angina indicate that Ad5FGF-4 increases treadmill exercise duration and improves stress-related ischemia measured by perfusion sestamibi single-photon emission computed tomography. More patients receiving Ad5FGF-4 than placebo reported complete resolution of their angina and no nitroglycerin use. Ad5FGF-4 gene therapy was well tolerated. The administration procedure did not cause any adverse events, although mild, transient fever, a transient modest fall in platelet count, and a transient mild elevation in hepatic enzymes and uric acid levels occurred in a few patients. This adverse event profile concurs with other adenoviral gene trials. There was no evidence of myocarditis, retinal neovascularization, or angioma formation. FGF-4 was not detected in venous blood. Larger clinical trials will assess Ad5FGF-4 with regard to cardiovascular prognosis, symptom relief, and safety profile in patients with chronic stable angina.
Grines
Cindy
C
William Beaumont Hospital, Royal Oak, Michigan 48073, USA. cgrines@beumont.edu
Rubanyi
Gabor M
GM
Kleiman
Neal S
NS
Marrott
Pran
P
Watkins
Matthew W
MW
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003326:Coronary Circulation / Q000502:physiology; D003327:Coronary Disease / Q000628:therapy*; D005080:Exercise Test; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D018919:Neovascularization, Physiologic; D016277:Ventricular Function, Left
D005346:Fibroblast Growth Factors