VEGF Gene Therapy Fails to Improve Perfusion of Ischemic Myocardium in Patients With Advanced Coronary Disease: Results of the NORTHERN Trial

Abstract

Despite the promise of proangiogenic gene therapy most clinical trials have failed to show benefit for the primary end point analysis. The NOGA angiogenesis Revascularization Therapy: assessment by RadioNuclide imaging (NORTHERN) trial was a double-blind, placebo-controlled study of intramyocardial vascular endothelial growth factor (VEGF165) gene therapy versus placebo, involving seven sites across Canada, designed to overcome major limitations of previous proangiogenic gene therapy trials. A total of 93 patients with refractory Canadian Cardiovascular Society (CCS) class 3 or 4 anginal symptoms were randomized to receive 2,000 microg of VEGF plasmid DNA or placebo (buffered saline) delivered via the endocardial route using an electroanatomical NOGA guidance catheter. There was no difference between the VEGF-treated and the placebo groups in the primary end point of change in myocardial perfusion from baseline to 3 or 6 months, assessed by single photon emission tomography (SPECT) imaging, although a significant reduction in the ischemic area was seen in both groups. Also, similar improvements in exercise treadmill time and anginal symptoms were seen in the VEGF and the placebo groups at 3 and 6 months, although again there were no differences between these groups. Despite the intramyocardial administration of a high "dose" of plasmid DNA using a percutaneous guidance catheter system, there was no benefit of VEGF gene therapy at 3 or 6 months for any of the end points studied.

Terapia gênica com VEGF para angiogênese na angina refratária: ensaio clínico fase I/II

“…Other authors have reported the safety procedures [19][20][21]. However, this information is important because it was done in our midst and with technical peculiarities of the surgical procedure, and, previously, only assays were performed in Brazil [23,24].…”

“…The vascular endothelial growth factor (vascular endothelial growth factor -VEGF) has been the focus of several studies [5,6] and its effects are being tested in patients with severe CAD [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Studies use different doses, vectors and ways Conclusions: The therapy has proved to be safe and feasible in this series of patients.…”

“…Three months after intervention we observed improvements in scintigraphic SSS scores (18.38 ± 7.51 vs. 15.31 ± 7.29, P = 0.003) and SRS (11.92 ± 7.49 vs. 8.53 ± 6.68, P = 0.002) but not in proportion to the areal extent of ischemic Rev Bras Cir Cardiovasc 2010; 25(3): 311-321 of administration of VEGF. Clinical trials bring controversial results, many showing evidence of clinical improvement and angiogenesis [8][9][10][11][12][13][14][15][16][17][18][19] and others showing no differences in myocardial perfusion when compared to their controls [7,20]. Thus, although promising, remain still not completely clear the clinical effects on the myocardium vascularization of the therapy with VEGF in its various forms and ways of administration, justifying further studies.…”

Physiological and tissue-specific vectors for treatment of inherited diseases

“…However, phase II/III studies did not confirm these initial results. 90 Endothelium-specific vectors can also be an alternative to liver-and muscle-specific vectors for systemic expression. Both natural (vWF, FLT-1 and ICAM-2) and synthetic promoters have been used to drive endothelium-specific expression by viral and nonviral vectors.…”

Disruption of VEGF Mediated Flk‐1 Signaling Leads to a Gradual Loss of Vessel Health and Cardiac Function During Myocardial Infarction: Potential Therapy With Pellino‐1

“…We also noted an improved cardiac functions as assessed by echocardiography. However, our interest shifted from VEGF to the molecules downstream of VEGF that may be involved in angiogenesis after clinical trials of VEGF failed to yield similar outcomes in patients with cardiovascular disease 5, 6, 7…”