Angiogenesis Using VEGF-A165/bFGF Plasmid Delivered Percutaneously in No-option CAD Patients; a Controlled Trial

Summary

Achieving therapeutic angiogenesis with gene therapy using a plasmid coding human VEGF-A165/bFGF injected into ischemic myocardium of refractory coronary artery disease patients, employing a percutaneous catheter-based technique- a double-blind placebo controlled study. Some patients with persistent coronary artery disease cannot be effectively treated using methods available today ("no-option" patients). It is currently evident that an emerging therapy for them might be the stimulation of neoangiogenesis in the area of ischemic myocardium using growth factor genes. Agents attracting greatest interest are FGF (fibroblast growth factor) and VEGF (vascular-endothelial growth factor). A number of methods have been tested to deliver these agents to the area of interest. Basic research has revealed that potent forms of angiogenic growth factors are the basic FGF (bFGF) and VEGF type A. Most clinical research on therapeutic angiogenesis is done using one of these two growth factors. This is to our knowledge the first clinical study using bicistronic VEGF-A 165/bFGF plasmid. Patient population will comprise CCS III and CCS IV coronary artery disease patients who cannot be treated with standard revascularization methods. In the course of study we shall attempt to analyze the efficacy of therapeutic plasmid-induced angiogenesis in terms of myocardial perfusion increase and clinical symptom improvement. The feasibility and safety of plasmid delivery method will also be assessed. A percutaneous catheter-based technique (Myo-Star, Johnson \& Johnson®) is used for plasmid delivery. All patients enrolled will receive optimal medical treatment as judged by treating physician. An effort will be made to modify medical therapy during the study course only for clear reasons. Standard angiography and ventriculography will be performed prior to plasmid injection therapy. Ischemic area of interest will be identified on inclusion by SPECT. Cardiac nuclear magnetic resonance (cNMR) with adenosine will also be performed to assess heart morphology, function and perfusion. Next, injections will be performed according to protocol. Follow-up visits will be performed at month 4 and month 12 after injection therapy. A change in myocardial perfusion at rest and on dipyridamole-stress SPECT evaluation after injection therapy will be the primary measure of efficacy. Changes in exercise tolerance will also be monitored along with a number of other efficacy and safety parameters.

Timeline

Start

2004-12

Primary completion

2008-05

Completion

2009-05

Outcome

Missed primary endpoint

paper Bicistronic VEGF/FGF plasmid therapy did not improve myocardial perfusion measured by single-photon emission computed tomography. PMID 21392615 ↗

Publications

• Background Kukula, K., Dabrowski, M., Chojnowska, L., Chmielak, Z., Witkowski, A., Skwarek, M., Kadziela, J., Malecki, M., Teresinska, A., Kownacki, L., Piotrowska-Kownacka, D., Ruzyllo, W., Theoretical base and investigational plan of the VIFCAD study- gene therapy for refractory coronary artery disease in no-option patients using transendocardial bicistronic VEGF/FGF plasmid injection. Post Kardiol Interw; 2, 1 (2006) 116-123
• Kukula K, Urbanowicz A, Klopotowski M, Dabrowski M, Pregowski J, Kadziela J, Chmielak Z, Witkowski A, Ruzyllo W. Long-term follow-up and safety assessment of angiogenic gene therapy trial VIF-CAD: Transcatheter intramyocardial administration of a bicistronic plasmid expressing VEGF-A165/bFGF cDNA for the treatment of refractory coronary artery disease. Am Heart J. 2019 Sep;215:78-82. doi: 10.1016/j.ahj.2019.06.009. Epub 2019 Jun 19.
• Kukula K, Chojnowska L, Dabrowski M, Witkowski A, Chmielak Z, Skwarek M, Kadziela J, Teresinska A, Malecki M, Janik P, Lewandowski Z, Klopotowski M, Wnuk J, Ruzyllo W. Intramyocardial plasmid-encoding human vascular endothelial growth factor A165/basic fibroblast growth factor therapy using percutaneous transcatheter approach in patients with refractory coronary artery disease (VIF-CAD). Am Heart J. 2011 Mar;161(3):581-9. doi: 10.1016/j.ahj.2010.11.023. Epub 2011 Jan 31.

Drugs

Indications