Safety and Feasibility of Catheter-Based Local Intracoronary Vascular Endothelial Growth Factor Gene Transfer in the Prevention of Postangioplasty and In-Stent Restenosis and in the Treatment of Chronic Myocardial Ischemia

Abstract

Background— Catheter-based intracoronary vascular endothelial growth factor (VEGF) gene transfer is a potential treatment for coronary heart disease. However, only limited data are available about local VEGF gene transfer given during angioplasty (PTCA) and stenting. Methods and Results— Patients with coronary heart disease (n=103; Canadian Cardiovascular Society class II to III; mean age, 58±6 years) were recruited in this randomized, placebo-controlled, double-blind phase II study. PTCA was performed with standard methods, followed by gene transfer with a perfusion-infusion catheter. Ninety percent of the patients were given stents; 37 patients received VEGF adenovirus (VEGF-Adv, 2×10 10 pfu), 28 patients received VEGF plasmid liposome (VEGF-P/L; 2000 μg of DNA with 2000 μL of DOTMA:DOPE [1:1 wt/wt]), and 38 control patients received Ringer’s lactate. Follow-up time was 6 months. Gene transfer to coronary arteries was feasible and well tolerated. The overall clinical restenosis rate was 6%. In quantitative coronary angiography analysis, the minimal lumen diameter and percent of diameter stenosis did not significantly differ between the study groups. However, myocardial perfusion showed a significant improvement in the VEGF-Adv-treated patients after the 6-month follow-up. Some inflammatory responses were transiently present in the VEGF-Adv group, but no increases were detected in the incidences of serious adverse events in any of the study groups. Conclusions— Gene transfer with VEGF-Adv or VEGF-P/L during PTCA and stenting shows that (1) intracoronary gene transfer can be performed safely (no major gene transfer-related adverse effects were detected), (2) no differences in clinical restenosis rate or minimal lumen diameter were present after the 6-month follow-up, and (3) a significant increase was detected in myocardial perfusion in the VEGF-Adv-treated patients.

Hybrid vector including polyethylenimine and cationic lipid, DOTMA, for gene delivery

“…DOTMA is a cationic lipid used as a gene delivery liposome (Felgner et al, 1984;Wollenberg et al, 1999;Hedman et al, 2003). The particle size of the complex was significantly reduced by DOTMA addition and settled to 74-114 nm, indicating pDNA compaction (Table 1).…”

Concise Review: Mending a Broken Heart: The Evolution of Biological Therapeutics

“…Most gene therapy clinical trials for CAD were focused on the administration of genes encoding angiogenic growth factors, such as VEGF and FGF4, aiming to promote the development of collateral blood vessels in ischemia-related conditions. Early trials, such as VIVA [53] and KAT [52], suggested a functional improvement in myocardial perfusion and cardiac function in patients with CAD after the administration of either an expression plasmid or an adenoviral vector expressing VEGF-A 165 , respectively. However, subsequent, double-blind, randomized, placebo-controlled studies (EUROINJECT-ONE, NORTHERN) [55,56] failed to demonstrate any improvement in myocardial perfusion.…”

Gene Therapy in Cardiovascular Disease

“…One of the main problems with the use of plasmid DNA, is the lack of response with an increasing dosage . The use of this vector, is considered relatively safe, but it has demonstrated in animal models that it can produce fever, inflammation and infarcts in the skeletal muscle and in the myocardium (Hedman et al, 2003). DNA and RNA oligonucleotides potential to be used as decoys, were mentioned over 10 year ago, but their minimum effectiveness in tissues, also discards them for some clinical application (Alexander et al, 2005).…”

“…Likewise the possibility of perform transference of genomic material in vivo, has been made possible exploring this technique as an option to correct the defects present in CVD, under the premise of being a therapy able to correct the underlying defects present in the failing heart. Although the treatment by transference of genetic material still presents many challenges, small clinical tests have already been performed, applying angiogenic factors in ischemic cardiomyopathy (Hedman et al, 2003;Kastrup et al, 2005;Stewart et al, 2006). In relation to other molecular mechanisms of the HF, as it is mentioned below, several of them are in clinical phases in different stages of proximity to a wider clinical setting.…”