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Vascular endothelial growth factor (VEGF)-mediated gene therapy (GT) has shown promising results as a novel method in the treatment of severe cardiovascular diseases. VEGF GT has proved to be safe and well tolerated in short-term studies, but there is only very limited data available on long-term effects. In this study we examined the effects of VEGF GT on patients having received VEGF-A gene transfer for the treatment of symptomatic (that is, claudication or critical lower limb ischemia) peripheral arterial occlusive disease. Out of 54 patients, 25 (46%) were interviewed for this study and 26 (48%) had died during the follow-up. Interviewed patients were treated with adenoviral (n=8, mean age 76 (62.7-90.6) years) or plasmid/liposome (n=8, mean age 84.2 (71.9-94.7) years) vectors compared with a randomized control group (n=10, mean age 80.5 (70.7-88.1) years) using a local balloon catheter device. The follow-up time was 10 years. Causes of death were clarified from hospital records. There were no statistically significant differences between the study groups in the causes of death or in the incidence of cancer (VEGF-Adv 0/10 vs VEGF-p/l 1/8 vs Control 1/7, P=0.5), diabetes (3/10 vs 3/8 vs 2/7, P=1.00) or diabetic retinopathy (0/10 vs 1/8 vs 0/7, P=0.45). In addition, we found no differences in the number of amputations of the treated leg (0/10 vs 3/8 vs 1/7, P=0.17). We conclude that transient VEGF-A-mediated GT did not increase the incidence of cancer, diabetes, retinopathy or any other diseases during the 10-year follow-up time. No significant differences were detected in the number of amputations or causes of death. This study supports our previous findings that local adenovirus and plasmid/liposome-mediated VEGF-A GT is safe and well-tolerated treatment in elderly patients with cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Several gene therapy approaches have been designed for the treatment of cardiovascular diseases. A positive finding is that the safety of cardiovascular gene therapy has been excellent even in long-term follow-up. However, several hurdles to this field are still present. A major disappointing feature of the trials is that while preclinical and uncontrolled phase-I gene therapy trials have been positive, none of the randomized controlled phase-II/III cardiovascular gene therapy trials have shown clinically relevant positive effects. Low gene transfer efficiency seems to be associated with several trials. A sophisticated efficient delivery method for cardiovascular applications is still lacking and only low concentrations of the gene product are produced in the target tissues. Only a few gene therapy vectors can be produced in large scale. In addition, inflammatory reactions against vectors and inability to regulate gene expression are still present. Furthermore, a strong placebo effect is affecting the results in gene therapy trials, and long-term trials have become more difficult to conduct because of the multiplicity of therapies applied simultaneously on the patients. This review summarizes advances and obstacles of current cardiovascular clinical gene therapy trials. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF) has been shown to stimulate angiogenesis and myocardial perfusion. The short-term safety of VEGF gene therapy is excellent. However, there are only limited results regarding the long-term effects. The Kuopio Angiogenesis Trial (KAT) studied the efficiency and short-term safety of the local VEGF-A165 gene transfer in 103 patients with coronary artery disease. Three patient groups received either VEGF as an adenoviral (n=37), or as a plasmid/liposome vector (n=28), or as a placebo (n=38), during coronary angioplasty and stenting (percutaneous coronary intervention, PCI)AQ1. The aim of this study was to examine the long-term effects and safety of VEGF gene therapy. Patients were interviewed by telephone or with a questionnaire on their current status of health, coronary and other cardiovascular events and symptoms, working ability, exercise tolerance, other diseases, such as cancer and diabetes, as well as their personal experience of the treatment. Causes of death were clarified from hospital records. The total follow-up time was 8.1 years (range 6.9–9.7 years). Overall 82% of the patients were reached across the study. Eight (7.5%) of the patients died during the follow-up, but there was no significant difference in mortality between the groups (3/32 vs 2/26 vs 3/31 VEGF-adenovirus vs VEGF-plasmid/liposome vs placebo, respectively; P=0.88). The incidence of major adverse cardiovascular events (MACEs) (10 vs 11 vs 15; P=0.85), cancer (1 vs 4 vs 2; P=0.38) or diabetes (2 vs 2 vs 2; P=0.97) did not differ between the groups. Local intracoronary VEGF gene transfer is safe and does not increase the risk of MACE, arrhythmias, cancer, diabetes or other diseases.Gene Therapy (2009) 16, 629–634; doi:10.1038/gt.2009.4; published online 12 February 2009 [ABSTRACT FROM AUTHOR]

This study was performed to evaluate angiogenic responses of angiopoietin-1 (Ang1) in vivo after adenovirus-mediated gene transfer in the periadventitial space of the rabbit carotid arteries using a collar technique. Adenoviruses encoding LacZ and vascular endothelial growth factor (VEGF) receptor-1-Ig fusion protein (VEGF-R1-Ig) adenoviruses were used as controls. Increased neovessel formation was seen in adventitia of the Ang1 transduced arteries 7 days after the gene transfer. Neovessels in the Ang1 transduced arteries were large in size and well perfused. Ang1 binds to Tie2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domain) receptors, which were expressed in the endothelium of the neovessels. When VEGF-R1-Ig was used with Ang1, it resulted in a decrease in the number of neovessels, which implies that VEGF-A or some other VEGF-R1 ligand(s) play a crucial role in angiogenesis occurring in response to Ang1. There were no significant differences in the total number of capillaries in the adventitia of the VEGF-R1-Ig transduced arteries as compared to LacZ controls. Neointima formation was not increased in the Ang1 transduced arteries as compared to the controls. We conclude that in the periadventitial space Ang1 shows angiogenic activity and is a potentially useful factor for the induction of therapeutic vascular growth in vivo.Gene Therapy (2005) 12, 388-394. doi:10.1038/sj.gt.3302426 Published online 13 January 2005 [ABSTRACT FROM AUTHOR]